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Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer's disease
Abstract
We examined the effects of voluntary (16 weeks of wheel running) and forced (16 weeks of treadmill running) exercise on memory-related behavior, hippocampal volume, thioflavine-stained plaque number, and soluble Abeta levels in brain tissue in the Tg2576 mouse model of Alzheimer's disease (AD). Voluntary running animals spent more time investigating a novel object in a recognition memory paradigm than all other groups. Also, voluntary running animals showed fewer thioflavine S stained plaques than all other groups, whereas forced running animals showed an intermediate number of plaques between voluntary running and sedentary animals. Both voluntary and forced running animals had larger hippocampal volumes than sedentary animals. However, levels of soluble Abeta-40 or Abeta-42 did not significantly differ among groups. The results indicate that voluntary exercise may be superior to forced exercise for reducing certain aspects of AD-like deficits - i.e., plaque deposition and memory impairment, in a mouse model of AD.
... Mice exposed to social, physical, and cognitive training show a protective effect against cognitive impairment, decreased brain Aβ burden, and enhanced hippocampal synaptic immunoreactivity [24,25]. Additionally, physical exercise in isolation has been shown to reduce AD pathology and improve memory in various murine models of AD [26,27]. ...
... The findings from the present study are consistent with other work assessing the benefits of exercise in mouse models of AD. One study reported that voluntary exercise for 16 weeks improved the memory function of Tg2576 mice and evidence also suggests that voluntary exercise over forced exercise was more effective [27] (using treadmill). In another study, results showed the beneficial effect of exercise in the Tg4-42 mouse model of AD on MWT and NOR tests, although it should be noted that these experiments combined exercise with an enriched environment [26]. ...
... In another experiment, Adlard and colleagues also reported that TgCRND8 mice with wheel running access for 5 months showed reduction in amyloid pathology which they argued might be responsible for the cognitive improvements observed [63]. Other studies are also consistent with this claim that exercise can reduce amyloid load [22,27,63]. ...
Background
An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer’s disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise.
Methods
Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells.
Results
The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise.
Conclusion
These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD.
... Carla M et al, examined the effects of voluntary (16 weeks of wheel running) and forced (16 weeks of treadmill running) exercise on mouse model of Alzheimer's disease. The results indicate that voluntary exercise is more beneficial for mitigating the behavioral and neuropathological components of the AD process than forced exercise (21). However, the beneficial effect of exercise type, its duration, intensity and frequency is also unclear (14). ...
... Training Protocol: The voluntary exercise group was placed in a rotating wheel, and the distance traveled per day was recorded by the device in meters per minute. VW (Voluntary wheel running, for eight weeks, three sessions per week and 60 minutes each session) had done (21). ...
... However, the study, conducted by Baghan et al., concluded that voluntary exercise could be useful as a non-pharmacological treatment for mental and emotional disorders such as anxiety, and showed that voluntary exercise was significantly better than forced exercise and it eliminated anxiety and reduced gene expression of inflammatory factors in the brain (6). Studies have shown that exercise has a big effect on the structure and function of the CNS, possibly by increasing the expression and production of brain-derived neuronal growth factor (BDNF), neurogenesis and synaptogenesis, reducing inflammatory factors, increasing serotonergic system activity and reducing stress (1,21,35,36). Reducing oxidative stress leads to morphological and behavioral changes and has anti-anxiety effects (37). Since the hippocampus is one of the most important structures in the brain associated with depressive and anxiety behaviors (30), it can also be noted that reducing anxiety following exercises can result in changes in the hippocampus because it has been shown that running increases the number of new stimulatory neurons and more dendritic branches throughout the hippocampal circuit (8). ...
Background & Objective: Alzheimer is a neurodegenerative disease in which numerous changes occur in the patient's brain, since it is suggested that royal jelly (RJ) and Physical activity have several pharmacological activities, including neuroprotective and improvement of cognitive function. This study aimed to investigate the effect of eight weeks of voluntary wheel running exercise with royal jelly consumption on behavioral disorders and antioxidant capacity in rats with Trimethytin model of Alzheimer’s disease.
Materials & Methods: This experimental study was performed on 48 male rats; Alzheimer's Trimethytin was induced on 40 rats. The rats were then randomly divided into six groups each group consisting of 8 members: healthy control group (HC), Alzheimer control group (ADC), voluntary exercise (VW) (wheel running), sham (SH), voluntary exercise combined with the royal jelly intake (VWJ) and royal jelly intake (RJ). Voluntary wheel running was done for eight weeks, three sessions per week and 60 minutes each session. To determine depression and anxiety, The Forced Swimming Test (FST) and Elevated Plus-Maze (EPM) were used respectively. Real-Time PCR was used to determine Gene expression of Superoxide dismutase (SOD) and Glutathione peroxidase (GPX). Data analysis was performed by the multivariate analysis of variance (MANOVA) test and post hoc Scheffe at the significance level of P
... Overall, CPE facilitates brain plasticity. A running training program in mice with AD (60 min, 5 sessions a week, 16 weeks) increased the hippocampal volume [F(3,31) = 4.577; p = 0.009] more than in control non-trained subjects [61]. On the basis of old trained and nontrained mice, it has been observed that the hippocampal neurogenesis is associated with synaptogenesis [5]. ...
... For example, the concentration of amyloid plaques in the brains of mice and the impairment of their memory capacity decreased more when they ran freely in a wheel (i.e. without a predefined speed of rotation) than when they ran at a predefined speed (i.e. at a forced speed) [61]. This means that the beneficial effects of CPE on brain function are not only generated by cardiovascular adaptations, but are also regulated by other factors such as motivation (for example). ...
Introduction:
The preventive effects of chronic physical exercise (CPE) on Alzheimer's disease (AD) are now admitted by the scientific community. Curative effects of CPE are more disputed, but they deserve to be investigated, since CPE is a natural non-pharmacological alternative for the treatment of AD.
Areas covered:
In this perspective, the authors discuss the impact of CPE on AD based on an exhaustive literature search using the electronic databases PubMed, ScienceDirect and Google Scholar.
Expert opinion:
Aerobic exercise alone is probably not the unique solution and needs to be complemented by other exercises (physical activities) to optimize the slowing down of AD. Anaerobic, muscle strength and power, balance/coordination and meditative exercises may also help to slow down the AD progression. However, the scientific evidence does not allow a precise description of the best training program for patients with AD. Influential environmental conditions (e.g. social relations, outdoor or indoor exercise) should also be studied to optimize training programs aimed at slowing down the AD progression.
... Another study showed that 3-week voluntary running wheel does not change levels of insoluble amyloid beta (Aβ1-40, Aβ1-42) in the brain (hippocampus) of Alzheimer's rats [24]. In addition, 4 months of forced and voluntary running had no significant effects on levels of soluble Aβ (Aβ1-40, Aβ1-42) in the cortex and hippocampus of Alzheimer's rats [25]. However, followed by 5 months of voluntary running wheel significant reduction was observed in the extracellular Aβ plaques in the frontal cortex and hippocampus and cortex of Alzheimer's rats [26]. ...
... Brain tissue was frozen by liquid nitrogen at 80ºC. The homogenized brain tissue was centrifuged at the speed of 10,000 rpm for 5 minutes [25]. ...
Background: Amyloid Beta (1-42) is derived from amyloid precursor protein and plays a critical role in AD pathogenesis. The purpose of this study was to investigate the effect of 6 weeks of voluntary wheel running on brain Amyloid beta (1-42) in the diabetic rats induced with alloxan. Materials and Methods: 28 male rats weight 185±1 were assigned randomly to 4 groups (N=7): normal control (C), training (T), control-diabetic (CD) and diabetic-training (DT). Diabetes was induced with injecting Alloxan (120 mg/kg dissolved in saline) intraperitoneal. Results: 6 weeks of voluntary wheel running decreased the cortex Aβ 1-42 in T and DT groups. Aβ 1-42 levels significantly decreased in the T and DT in compare with C and CD (p<0.001), respectively. Also Aβ 1-42 levels significantly increased in the CD in compare with C (p<0.001). Conclusion: voluntary exercise had positive effects on decreasing of Aβ 1-42 levels during 6 weeks. Therefore it can be recommended as therapeutic strategy for diabetes.
... There is evidence indicating that regular exercise led to diminished oxidative stress in experimental animals with cerebral ischemia (Cechetti et al., 2012), seizure (Souza et al., 2009), and parkinson disease (Lau et al., 2011), as well as alleviated neuroinflammation in traumatic brain injury of mice (Mota et al., 2012). In transgenic mice models of AD, having physical exercise resulted in enhanced memory (Parachikova et al., 2008;García-Mesa et al., 2011;Liu et al., 2011;Um et al., 2011), reduced inflammation (Parachikova et al., 2008), and apoptosis markers (Um et al., 2011), elevated expression of antioxidant enzymes in hippocampus (Um et al., 2011), and decreased amyloid deposit in cerebral cortex (Yuede et al., 2009). Large muscle groups are engaged in aerobic exercises like running, swimming, cycling, and walking as the dynamic physical actions requiring free oxygen and focusing on increased cardiovascular endurance (Plowman and Smith, 2013;Ö zbeyli and Çakır, 2017). ...
... As an example, treadmill running training has been shown to prevent in the reduction of spatial memory in the course of water maze test in the APP/PS1 transgenic murine model of AD (Liu et al., 2011). Concerning ORT, Yuede et al. (2009) found that both voluntary exercise (16 weeks of wheel running) and forced training (16 weeks of treadmill running) enhanced the function of recognizing new object in the Tg2576 murine model of AD. An improved object recognition memory as a result of exercise training was also proved in sound rats (García-Capdevila et al., 2009;Hopkins and Bucci, 2010), by utilizing wheel running as a prototype of exercise. ...
Heavy metals are considered contaminants that hazardously influence the healthy life of humans and animals as they are widely used in industry. Contact of youngsters and women at ages of parturition with lead (Pb+2) is a main related concern, which passes through the placental barricade and its better absorption in the intestine leads to flaws in the fetal developfment. However, the metals threaten animal and human life, in particular throughout developmental stages. Products existing in the nature have a major contribution to innovating chemo-preventives. As a naturally available polyphenol and necessary curcuminoid, curcumin (Cur) is a derivative of the herb Curcuma longa (L.) rhizome, which globally recognized as “wonder drug of life”; however, Cur has a limited clinical use as it is poorly dissolved in water. Therefore, to enhance its clinically relevant parameters, curcumin-loaded calcium carbonate (CaCO3@Cur) was synthesized by one step coprecipitation method as a newly introduced in this research. Initially, its structure was physio chemically characterized using FT-IR, FESEM and DLS equipment and then the cytotoxicity of lead when it was pretreated with Cur/CaCO3@Cur were assessed by MTT assay. Both Cur and CaCO3@Cur diminished the toxic effects of Pb+2 while the most protective effect on the Pb+2 cytotoxicity was achieved by pre-incubation of cells with CaCO3@Cur. Besides, the morphological changes of Pb+2-treated cells that were pre-incubated with or without Cur/CaCO3@Cur were observed by normal and florescent microscopes. A non-pharmacologic method that lowers the hazard of brain damage is exercise training that is capable of both improving and alleviating memory. In the current study, the role of regular aerobic training and CaCO3@Cur was assessed in reducing the risk of brain damage induced by lead nitrate contact. To achieve the mentioned goal, pregnant Balb/C mice were assigned to five groups (six mice/group) at random: negative and positive controls, aerobic training group and Cur and CaCO3@Cur treated (50 mg/kg/b.wt) trained groups that exposed to Pb+2 (2 mg/kg) by drinking water during breeding and pregnancy. With the completion of study, offspring were subjected to the behavioral tasks that was tested by step-through ORT, DLB, MWM and YM tests. As a result, having regular aerobic training and CaCO3@Cur co-administration with lead nitrate could reverse the most defected behavioral indicators; yet, this was not visible for both sexes and it seems that gender can also be a source of different effects in the animal's body. In fact, having regular aerobic training along with CaCO3@Cur supplementation during pregnancy may be encouraging protecting potential agents towards the toxicity of Pb+2 that could be recommended in the areas with high pollution of heavy metals.
... A battery of sensorimotor tests was used to screen for differences in balance, coordination, motor function, or other non-associative factors that could confound interpretation of the cognitive tests. Spatial learning and memory were evaluated in the Morris Water Maze task, and recognition memory was assessed in a novel object recognition task based on previously published methods (Wozniak et al., 2004(Wozniak et al., , 2013Yuede et al., 2009). ...
... Pilot studies were conducted to evaluate the level of interest of specific objects and two different objects showing equal interest levels were chosen for this study (glass votive and metal basket) similar to (Yuede et al., 2009). Mice were habituated to the test arena (8.5 × 17 × 8 in) ...
Amyloid‐β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT2A‐Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real‐time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT2A‐R knock‐out mice. The Aβ‐lowering effects of Pimavanserin were blocked by extracellular‐regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA‐approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease‐modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease.
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... 175 Unfortunately, neither concurrent treatment with a candidate drug (rapamycin or metformin) nor forced exercise were able to prevent the observed persistent hypoxia-induced losses of function. In particular, given the general belief that exercise provides beneficial effects to the cardiopulmonary system as well as an extensive literature regarding its beneficial remodeling of the aorta in the context of systemic hypertension, [176][177][178][179][180][181][182][183][184] we were surprised that adjuvant exercise during recovery from chronic hypoxia in juvenile mice ("early exposure" group) had no effect and only partially beneficial effects in maintaining PPA wall thickness and radius of adult mice ("later exposure" group). Further, adjuvant exercise had mixed effects on recovery of functional indices of the pulmonary vasculature as well as lung and RV functions. ...
Hypoxemia impairs cardiopulmonary function. We investigated pulmonary artery remodeling in mice exposed to chronic hypoxia for up to five weeks and quantified associated changes in cardiac and lung function, without or with subsequent normoxic recovery in the absence or presence of exercise or pharmacological intervention. Hypoxia-induced stiffening of the proximal pulmonary artery stemmed primarily from remodeling of the adventitial collagen, which resulted in part from altered inter-cellular signaling associated with phenotypic changes in the mural smooth muscle cells and macrophages. Such stiffening appeared to precede and associate with both right ventricular and lung dysfunction, with changes emerging to similar degrees regardless of the age of onset of hypoxia during postnatal development. Key homeostatic target values of the wall mechanics were recovered by the pulmonary arteries with normoxic recovery while other values recovered only partially. Overall cardiopulmonary dysfunction due to hypoxia was similarly only partially reversible. Remodeling of the cardiopulmonary system due to hypoxia is a complex, multi-scale process that involves maladaptations of the proximal pulmonary artery.
... APP SWE mice also exhibit impaired AHN that is mediated by Aβ expression in neural stem cells at prodromal stages (1.5 months) (Haughey et al., 2002;Scopa et al., 2020). Voluntary wheel running improves spatial learning and memory, decreases amyloid plaque formation, and increases hippocampal volume relative to sedentary APP SWE mice (Parachikova et al., 2008;Yuede et al., 2009;Walker et al., 2015). ...
JOURNAL/nrgr/04.03/01300535-202510000-00027/figure1/v/2024-11-26T163120Z/r/image-tiff
Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease. Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease. Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease. However, the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood. Recently, regulator of G protein signaling 6 (RGS6) was identified as the mediator of voluntary running–induced adult hippocampal neurogenesis in mice. Here, we generated novel RGS6 fl/fl ; APP SWE mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running–induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model. We found that voluntary running in APP SWE mice restored their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells, which also abolished running-mediated increases in adult hippocampal neurogenesis. Adult hippocampal neurogenesis was reduced in sedentary APP SWE mice versus control mice, with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells. RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons. Thus, RGS6 mediated voluntary running–induced rescue of impaired cognition and adult hippocampal neurogenesis in APP SWE mice, identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
... If the intervention occurs in the later stages of AD, the benefits of exercise in counteracting plaque formation and the deterioration of cognitive abilities are significantly reduced (Herring et al., 2016). Additionally, studies in mouse models suggest that voluntary exercise may be more beneficial than forced exercise for better treatment or alleviation of disease progression (Yuede et al., 2009). Emerging neuroimaging evidence further substantiates the neural impacts of physical exercise on AD, elucidating its role in modulating brain structure and function. ...
Introduction
Alzheimer’s disease (AD), a major cause of dementia globally, imposes significant societal and personal costs. This review explores the efficacy of physical exercise as a non-pharmacological intervention to mitigate the impacts of AD.
Methods
This review draws on recent studies that investigate the effects of physical exercise on neuroinflammation and neuronal enhancement in individuals with AD.
Results
Consistent physical exercise alters neuroinflammatory pathways, enhances cognitive functions, and bolsters brain health among AD patients. It favorably influences the activation states of microglia and astrocytes, fortifies the integrity of the blood-brain barrier, and attenuates gut inflammation associated with AD. These changes are associated with substantial improvements in cognitive performance and brain health indicators.
Discussion
The findings underscore the potential of integrating physical exercise into comprehensive AD management strategies. Emphasizing the necessity for further research, this review advocates for the refinement of exercise regimens to maximize their enduring benefits in decelerating the progression of AD.
... However, some studies show no change in MWM performance with late-stage exercise (Zhang et al., 2016;García-Mesa et al., 2016;Marlatt et al., 2013). One study found that voluntary exercise improved short-term memory, while forced exercise impaired memory and induced stress (Yuede et al., 2009;Kennard and Woodruff-Pak, 2012;Svensson et al., 2016). ...
... However, the specific impacts of exercise on the aging eye, particularly at the molecular level, are less well understood. Moreover, exercise can be categorized into voluntary (or recreational) and forced (or compulsory) forms, each potentially eliciting distinct physiological responses [24][25][26][27][28][29][30][31]. Voluntary exercise, characterized by selfinitiated activity, is thought to induce positive stress responses and adaptive mechanisms. ...
Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity. This study addresses the critical gap in our understanding of modifiable lifestyle factors, such as physical exercise, that may mitigate retinal aging and its related pathologies. We investigated the effects of different exercise regimens—voluntary (recreational-type) and forced (high-intensity)—on the retinal health of aging Wistar rats (18-month-old), serving as a model for studying the translational potential of exercise interventions in humans. Male Wistar rats were divided into four groups: a young control (3-month-old) for baseline comparison, an aged sedentary control, an aged group engaging in voluntary exercise via a running wheel in their cage, and an aged group subjected to forced exercise on a treadmill for six sessions of 20 min each per week. After a 6-month experimental period, we assessed retinal function via electroretinography (ERG), measured retinal thickness histologically, and analyzed protein expression changes relevant to oxidative stress, inflammation, and anti-aging mechanisms. Our findings reveal that voluntary exercise positively impacts retinal function and morphology, reducing oxidative stress and inflammation markers while enhancing anti-aging protein expression. In contrast, forced exercise showed diminished benefits. These insights underscore the importance of exercise intensity and preference in preserving retinal health during aging. The study highlights the potential of recreational physical activity as a non-invasive strategy to counteract retinal aging, advocating for further research into exercise regimens as preventative therapies for age-related ocular degenerations.
... Exercise has been shown to promote brain plasticity and improve cognitive function in both animal models and human studies [11][12][13][14]. Studies in various animal models have provided further insight into associated effects of exercise, showing reduced brain atrophy, promoted hippocampal neurogenesis, and reduced systemic and neuroinflammation [15][16][17][18]. ...
Background
Microglia and inflammation play a significant role in Alzheimer’s disease (AD). Physical exercise and peripheral signals can influence microglial activity in the brain. Modulating the inflammatory response in the brain may provide therapeutic approaches for AD.
Objective
To assess the effects of intravenously administered blood plasma from exercise-trained donor rats on cognitive function, microglia, and cytokine levels in an AD rat model at two different pathological stages; an early pre-plaque stage and a later stage closer to the emergence of extracellular plaques.
Methods
Male transgenic McGill-R-Thy1-APP rats aged 2 and 5 months received 14 injections over 6 weeks: 1) plasma from exercise-trained rats (ExPlas), 2) plasma from sedentary rats (SedPlas), or 3) saline. Cognitive function was evaluated in a novel object recognition task. Microglia count and morphology were analyzed in cornu ammonis, dentate gyrus, entorhinal cortex, and subiculum. Amyloid plaque number and size were assessed in the rats with the later treatment start. A multiplex assay was used to measure 23 cytokines in cornu ammonis.
Results
In rats treated from 2 months of age, ExPlas and SedPlas increased number and length of microglial branches in cornu ammonis and dentate gyrus compared to saline. Only ExPlas-treated rats exhibited similar changes in subiculum, while entorhinal cortex showed no differences across treatments. Microglia count remained unaffected. In rats treated from 5 months of age, there were no significant differences in microglia count or morphology or the number or size of amyloid plaques in any brain region. Compared to both other treatments in early pre-plaque stage rats, SedPlas increased TNF-α levels. ExPlas upregulated GM-CSF, IL-18, and VEGF, while SedPlas increased IL-10 compared to saline. In later-stage rats, ExPlas upregulated IL-17, and SedPlas upregulated TNF-α compared to saline. There were no effects of treatments on recognition memory.
Conclusions
Intravenous injections of blood plasma from exercise-trained and sedentary donors differentially modulated microglial morphology and cytokine levels in the AD rat model at an early pre-plaque stage of pathology. Exercised plasma may reduce proinflammatory TNF-α signaling and promote microglial responses to early Aβ accumulation but the lack of treatment effects in the later-stage rats emphasizes the potential importance of treatment timing.
... In addition, exercise training has been reported to reduce Aβ deposition and neuropathology in the hippocampus of AD animal models [31][32][33]. Our results indicate that exercise training alleviated Aβ deposition and possibly led to Purkinje cell survival. ...
Background
The cerebellum is an area of the brain that is prone to damage in individuals with Alzheimer’s disease (AD). As a non-pharmacological intervention for AD, exercise training has shown an ameliorating effect on AD pathology; however, the target regions have mostly been the cerebral cortex and hippocampus. The main aim of this study was to explore the influence of 12 weeks of treadmill running on the accumulation of AD-related proteins, dysfunction of mitochondria, and subsequent neuronal cell death in the cerebellum of triple transgenic (3xTg-AD) mice.
Methods
Four-month-old 3xTg-AD mice were allocated into two groups: an AD control group (AD, n = 10) and an AD exercise group (AD-Exe, n = 10). The AD-Exe mice underwent training on a motorized animal treadmill 5 days a week for 12 weeks. After sacrifice, the cerebellum was collected and biochemically analyzed.
Results
The AD-Exe mice expressed reduced levels of extracellular β-amyloid plaques and phosphorylated tau (p-tau), and showed improved Purkinje cell survival and mitochondrial function compared with AD mice.
Conclusions
These findings suggest that engaging in exercise training can offer protection against the progression of AD in the cerebellum by enhancing mitochondrial function and promoting cell survival.
... Voluntary and forced exercise groups have larger hippocampal volumes than sedentary animals. In other words, voluntary exercise is probably better for reducing Alzheimer's symptoms (such as plaque deposition and memory impairment) than forced exercise (Yuede et al., 2009). A controlled trial compared aerobic exercise 150 min per week (26 weeks) with anaerobic exercise in people with AD (mean age 72.9 years). ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disease in the elderly with dementia, memory loss, and severe cognitive impairment that imposes high medical costs on individuals. The causes of AD include increased deposition of amyloid beta (Aβ) and phosphorylated tau, age, mitochondrial defects, increased neuroinflammation, decreased synaptic connections, and decreased nerve growth factors (NGF). While in animals moderate-intensity exercise restores hippocampal and amygdala memory through increased levels of p-AKT, p-TrkB, and p-PKC and decreased levels of Aβ, tau phosphorylation, and amyloid precursor proteins (APP) in AD. Aerobic exercise (with an intensity of 50–75% of VO2 max) prevents hippocampal volume reduction, spatial memory reduction, and learning reduction through increasing synaptic flexibility. Exercise training induces the binding of brain-derived neurotrophic factor (BDNF) to TrkB and the binding of NGF to TrkA to induce cell survival and neuronal plasticity. After aerobic training and high-intensity interval training, the increase of VEGF, angiopoietin 1 and 2, NO, tPA, and HCAR1 in cerebral vessels causes increased blood flow and angiogenesis in the cerebellum, motor cortex, striatum, and hippocampus. In the hippocampus, exercise training decreases mitochondrial fragmentation, DRP1, and FIS1, improving OPA1, MFN1, MFN2, and mitochondrial morphology. In humans, acute exercise as an anti-inflammatory condition causes an acute increase in IL-6 and an increase in anti-inflammatory factors such as IL-1RA and IL-10. Moderate-intensity exercise also inhibits inflammatory markers such as IFN-γ, IL-1β, IL-6, CRP, TNF-α, sTNFR1, COX-2, and NF-κB. Aerobic exercise significantly increases plasma levels of BDNF, nerve growth factor, synaptic plasticity, motor activity, spatial memory, and exploratory behavior in AD subjects. Irisin is a myokine released from skeletal muscle during exercise and protects the hippocampus by suppressing Aβ accumulation and promoting hippocampal proliferation through STAT3 signaling. Therefore, combined exercise training such as aerobic training, strength training, balance and coordination training, and cognitive and social activities seems to provide important benefits for people with AD.
... In APP/PS1 mice, prolonged running in young leading to reductions in amyloid- plaque deposition [75,76,88,89]. These effects are also seen in Tg2576 mice [90,91]. Similarly, environmental enrichment in early life reduces amyloid- burden in AD11, cDKO, and PS1/PDAPP mice [77,78,92; but see 71,93]. ...
Background
Prior experience in early life has been shown to improve performance in aging and mice with Alzheimer’s disease (AD) pathology. However, whether cognitive training at a later life stage would benefit subsequent cognition and reduce pathology in AD mice needs to be better understood.
Objective
This study aimed to verify if behavioral training in mid-adulthood would improve subsequent cognition and reduce AD pathology and astrogliosis.
Methods
Mixed-sex APP/PS1 and wildtype littermate mice received a battery of behavioral training, composed of spontaneous alternation in the Y-maze, novel object recognition and location tasks, and spatial training in the water maze, or handling only at 7 months of age. The impact of AD genotype and prior training on subsequent learning and memory of aforementioned tasks were assessed at 9 months.
Results
APP/PS1 mice made more errors than wildtype littermates in the radial-arm water maze (RAWM) task. Prior training prevented this impairment in APP/PS1 mice. Prior training also contributed to better efficiency in finding the escape platform in both APP/PS1 mice and wildtype littermates. Short-term and long-term memory of this RAWM task, of a reversal task, and of a transfer task were comparable among APP/PS1 and wildtype mice, with or without prior training. Amyloid pathology and astrogliosis in the hippocampus were also comparable between the APP/PS1 groups.
Conclusion
These data suggest that cognitive training in mid-adulthood improves subsequent accuracy in AD mice and efficiency in all mice in the spatial task. Cognitive training in mid-adulthood provides no clear benefit on memory or on amyloid pathology in midlife.
... According to Hamer and Chida (2009) physical fitness reduces the ADrisk by 45% (22). In concordance, mice-and human studies suggest a neuroprotective effect of physical activity by reducing Aβ plaques, increasing hippocampal neurogenesis and improving memory performance (23)(24)(25)(26)(27)(28)(29). Several intervention-studies reported positive effects of physical exercise trainings on cognitive performance in patients with AD or MCI (20,(30)(31)(32)(33)(34). ...
Background
Training studies typically investigate the cumulative rather than the analytically challenging immediate effect of exercise on cognitive outcomes.
Methods
We investigated the dynamic interplay between single-session exercise intensity and time-locked cognition in older adults with suspected Alzheimer’s dementia (N = 17) undergoing a 24-week dual-task regime. We specified a state of the art hierarchical Bayesian continuous- time dynamic model with fully connected state variables to analyze the bidirectional effects between physical and cognitive performance over time.
Results
Higher physical performance was dynamically linked to improved memory recognition (-1.335, SD = 0.201, 95 BCI [-1.725, -0.954]). The effect was short-term, lasting up to five days (-0.368, SD = 0.05, 95 BCI [-0.479, -0.266]). Clinical scores supported the validity of the model and observed temporal dynamics.
Conclusion
Higher physical performance predicted improved memory recognition in a day- by-day manner, providing a proof-of-concept for the feasibility of linking exercise training and cognition in patients with Alzheimer’s dementia.
Highlights
Hierarchical Bayesian continuous-time dynamic modelling approach
72 repeated physical exercise (PP) and cognitive (COG) performance measurements
PP is dynamically linked to session-to-session variability of COG
Higher PP improved COG in subsequent sessions in subjects with Alzheimer’s dementia
Short-term effect: lasting up to four days after training session
Research in Context
Systematic review: Training-induced effects on cognitive outcomes in Alzheimer’s dementia and/or associated dynamic Bayesian modelling approaches were reviewed. Although studies showed exercise-induced cognitive improvements or maintenance, most of these studies fail to capture the dynamic nature of the change and interplay of physical (PP) and cognitive (COG) performance.
Interpretation: Using a sophisticated hierarchical Bayesian continuous-time dynamic modelling approach, a fully connected state variable model was specified. PP is dynamically linked to COG, i.e. higher PP predicted improved COG in subsequent sessions. This effect was rather short term, lasting for up to five days.
Future direction: Our results support exercise-induced effects on cognition. The cognitive system was still able to fluctuate and change favourably even in a sample with Alzheimer’s dementia. Further studies using dynamic modelling are necessary to replicate findings and examine other contributors to cognitive volatility in dementia.
... The evolution of the themes indicates that, since Teri et al. first proposed that exercise and an increased activity level can be a potential treatment for AD in 1998 [43], researchers have begun to pay attention to the beneficial impacts of exercise on cognitive impairment and the daily activity dysfunction of AD patients (e.g., [32,33,35,[44][45][46][47][48][49][50]), using mouse models to explore the effects of exercise on brain neural mechanisms (e.g., [13,31,34,39,[51][52][53][54][55]). These studies confirm that researchers have been trying to explore the potential protective mechanism of physical exercise on brain aging from mice to humans. ...
Alzheimer’s disease (AD) is the most common cause of dementia worldwide, posing a considerable economic burden to patients and society as a whole. Exercise has been confirmed as a non-drug intervention method in the related literature on AD. However, at present, there are still few bibliometric studies on AD exercise research. In order to fill the gap, this paper aims to intuitively analyze the growth in AD exercise literature published from 1998 to 2021 using bibliometrics, providing historical insights for scientific research circles. The main source of literature retrieval is the Web of Science database. Using the Boolean operator tools “OR” and “AND” combined with keywords related to “exercise” and “Alzheimer’s disease”, we conducted a title search and obtained 247 documents. Using Microsoft Excel, Datawrapper, and Biblioshiny, this study carried out a bibliometric analysis of countries, institutions, categories, journals, documents, authors, and keyword plus terms. The study found that the number of papers published from 2016 to 2021 had the greatest increase, which may have been influenced by the Global Dementia Report 2015 and COVID-19. Interdisciplinary cooperation and the research results published in high-scoring journals actively promoted research and development in the AD exercise field. The United States and the University of Minnesota system play a central role in this field. In future, it will be necessary to explore the effectiveness and feasibility of multi-mode interventions on an active lifestyle, including exercise, in different groups and environments worldwide. This study may provide a direction and path for future research by showing the global overview, theme evolution, and future trends of research results in the AD exercise field.
... Long-term treadmill exercise can better delay the progression of AD neuropathology in the hippocampus of APP/PS1 double transgenic mice . The effect of voluntary exercise in improving memory impairment due to AD is better than passive exercise training (Yuede et al., 2009). Long-term treadmill exercise also had positive effects on cognitive function and synaptic plasticity in APP/PS1 double transgenic mice . ...
Presenilin (Psn) protein is associated with organismal aging. Mutations in the Psn gene may lead to Alzheimer’s disease (AD), dilated cardiomyopathy (DCM), and many age-dependent degenerative diseases. These diseases seriously affect the quality of life and longevity of the population and place a huge burden on health care and economic systems around the world. Humans have two types of Psn, presenilin-1 (PSEN1) and presenilin-2 (PSEN2). Mutations in the genes encoding PSEN1, PSEN2, and amyloid precursor protein (APP) have been identified as the major genetic causes of AD. Psn is a complex gene strongly influenced by genetic and environmental factors. The effects of exercise, training, and a high-fat diet on the Psn gene expressed in the heart and its related pathways are not fully understood. Fortunately, relevant aspects of the mutational effects on Psn can be studied experimentally in easily handled animal models, including Drosophila, mice, and other animals, all of which share orthologous genes of Psn with humans. Many previous studies have linked aging, exercise training, and a high-fat diet to the Psn gene. This review discusses the interrelationship between aging, exercise training, and a high-fat diet on the Psn gene and its associated disease, AD. The aim is to understand the adverse effects of Psn gene mutations on the body and the diseases caused by AD, find ways to alleviate the adverse effects and provide new directions for the improvement of treatment strategies for diseases caused by Psn gene mutations.
... 13,17 Studies in mice show benefits of exercise to peripheral health, as well as improvements to cognitive function. [18][19][20][21][22][23][24][25][26][27] Though the cognitive changes due to exercise have been controversial, with human studies showing either no change or improvements with exercise, it is widely accepted that exercise affects the body in a generally positive manner (i.e., decreasing weight/fat mass, improving metabolism and circulation, and elevating mood). 19,[28][29][30][31][32][33] While understanding the effect of exercise on neuronal health is critical, other compartments of the brain are largely neglected. ...
Introduction:
Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease and related dementias (ADRDs), affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and APOE ε4 affect similar processes in the body and brain. While both APOE ε4 and exercise have been studied extensively, their interactive effects are not well understood.
Methods:
To address this, male and female APOE ε3/ε3, APOE ε3/ε4, and APOE ε4/ε4 mice ran voluntarily from wean (1 month) to midlife (12 months). Longitudinal and cross-sectional phenotyping were performed on the periphery and the brain, assessing markers of risk for dementia such as weight, body composition, circulating cholesterol composition, murine daily activities, energy expenditure, and cortical and hippocampal transcriptional profiling.
Results:
Data revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum low-density lipoprotein concentration dependent on APOE genotype. Additionally, murine daily activities and energy expenditure were significantly influenced by an interaction between APOE genotype and running in both sexes. Transcriptional profiling of the cortex and hippocampus predicted that APOE genotype and running interact to affect numerous biological processes including vascular integrity, synaptic/neuronal health, cell motility, and mitochondrial metabolism, in a sex-specific manner.
Discussion:
These data in humanized mouse models provide compelling evidence that APOE genotype should be considered for population-based strategies that incorporate exercise to prevent ADRDs and other APOE-relevant diseases.
... With previous studies suggesting that up to a third of LOAD cases may be prevented by physical activity, it is of the utmost importance to understand the interactions between genetic risk and exercise (Norton et al., 2014). To elucidate the effects of exercise on dementia related pathology, most exercise-based murine studies utilized amyloidogenic models relevant to AD or middle cerebral artery occlusion models of VaD (Yuede et al., 2009;Otsuka et al., 2016;Choi et al., 2018;Khodadadi et al., 2018;Rezaei et al., 2018;Zhang et al., 2018). The few studies that have determined whether exercise is beneficial in the context of APOE utilized mostly APOE knockout mice (Nichol et al., 2009;Soto et al., 2015;Di Cataldo et al., 2016;Jakic et al., 2019;Zheng and Cai, 2019;Chaudhari et al., 2020). ...
Introduction
Restrictions on existing APOE mouse models have impacted research toward understanding the strongest genetic risk factor contributing to Alzheimer’s disease (AD) and dementia, APOE ε4 , by hindering observation of a key, common genotype in humans – APOE ε3/ε4 . Human studies are typically underpowered to address APOE ε4 allele risk as the APOE ε4/ε4 genotype is rare, which leaves human and mouse research unsupported to evaluate the APOE ε3/ε4 genotype on molecular and pathological risk for AD and dementia.
Methods
As a part of MODEL-AD, we created and validated new versions of humanized APOE ε3/ε3 and APOE ε4/ε4 mouse strains that, due to unrestricted breeding, allow for the evaluation of the APOE ε3/ε4 genotype. As biometric measures are often translatable between mouse and human, we profiled circulating lipid concentrations. We also performed transcriptional profiling of the cerebral cortex at 2 and 4 months (mos), comparing APOE ε3/ε4 and APOE ε4/ε4 to the reference APOE ε3/ε3 using linear modeling and WGCNA. Further, APOE mice were exercised and compared to litter-matched sedentary controls, to evaluate the interaction between APOE ε4 and exercise at a young age.
Results
Expression of human APOE isoforms were confirmed in APOE ε3/ε3 , APOE ε3/ε4 and APOE ε4/ε4 mouse brains. At two mos, cholesterol composition was influenced by sex, but not APOE genotype. Results show that the APOE ε3/ε4 and APOE ε4/ε4 genotype exert differential effects on cortical gene expression. APOE ε3/ε4 uniquely impacts ‘hormone regulation’ and ‘insulin signaling,’ terms absent in APOE ε4/ε4 data. At four mos, cholesterol and triglyceride levels were affected by sex and activity, with only triglyceride levels influenced by APOE genotype. Linear modeling revealed APOE ε3/ε4 , but not APOE ε4/ε4 , affected ‘extracellular matrix’ and ‘blood coagulation’ related terms. We confirmed these results using WGCNA, indicating robust, yet subtle, transcriptional patterns. While there was little evidence of APOE genotype by exercise interaction on the cortical transcriptome at this young age, running was predicted to affect myelination and gliogenesis, independent of APOE genotype with few APOE genotype-specific affects identified.
Discussion
APOE ε4 allele dosage-specific effects were observed in circulating lipid levels and cortical transcriptional profiles. Future studies are needed to establish how these data may contribute to therapeutic development in APOE ε3/ε4 and APOE ε4/ε4 dementia patients.
... In a study that used familial AD gene mutations, exercise minimized neurotoxicity caused by AD neuropathy. Also, exercise stimulates neuronal regeneration and contributes to an improvement in cognitive functioning through a reduction in beta-secretase activity, decreased accumulation of amyloid plaques and soluble Aβ (Yuede et al., 2009). Therefore, this study investigated the effect of 40-Hz light flickering and exercise on insulin signaling and cell differentiation in the hippocampus of triple transgenic mouse model of Alzheimer disease (3xTg AD). ...
We examined whether exercise is associated with hippocampus-mediated improvement in insulin signaling and cell differentiation in the triple transgenic mouse model of Alzheimer disease (3xTg AD) murine model following exposure to 40-Hz light flickering and exercise. We subjected 12-month-old 3xTg AD mice to exercise and 40-Hz light flickering for 3 months. The exercise session was proceeded for 12 consecutive weeks with gradual increase of intensity. To investigate insulin signaling proteins, western blot was conducted to detect the ratio of phosphorylated insulin receptor β (p-IRβ)/total IRβ (t-IRβ), phosphorylated insulin receptor substrate 1 (p-IRS-1)/total IRS-1 (t-IRS-1), phosphorylated phosphatidylinositide-3-kinase (p-PI3K)/total PI3K (t-PI3K), phosphorylated 3-phosphoinositide dependent protein kinase-1 (p-PDK1)/total PDK-1 (t-PDK1), phosphorylated protein kinase B (p-Akt)/total-Akt (t-Akt), and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β)/total GSK3β (t-GSK3β). Doublecortin immunohistochemistry was performed for assessing cell differentiation in the hippocampus. Treatments exerted a positive effect. The combination of exercise and 40-Hz light flickering exposure was the most effective treatment enhancing insulin signaling. Increased ratio of p-IRβ/t-IRβ, p-IRS-1/t-IRS-1, p-PI3K/t-PI3K, p-PDK1/t-PDK1, p-Akt/t-Akt, and p-GSK3β/t-GSK3β and enhanced cell differentiation were observed in the 3xTg AD with exercise under 40-Hz light flickering group. Our results indicate that exercise under 40-Hz light flickering most potently improved insulin signaling, thereby promoted cell differentiation.
... Our study excluded experimental errors due to exercise intensity. Consistent with most articles [56,58], our results showed that longterm voluntary running significantly alleviated cognitive impairment, increased hippocampal volume in the DG and CA1 regions, reduced hippocampal Aβ deposition, and prevented synaptic loss in APP/PS1 mice. Emerging evidence has identified several targets for exercise to improve cognition in AD model mice [44,59]. ...
Background
The role of physical exercise in the prevention of Alzheimer’s disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear.
Methods
Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia.
Results
Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5 ⁺ /IBA1 ⁺ microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2′-deoxyuridine (BrdU) ⁺ /IBA1 ⁺ microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice.
Conclusions
Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.
... Aβ deposition and the accumulation of hyperphosphorylated Tau protein are two major pathological features of AD, so reducing Aβ deposition is believed to be one of the important targets of AD treatment. An exercise program of treadmill running and voluntary wheel running for 16 weeks was found to reduce the deposition of Aβ in the hippocampal tissue, improve learning and memory capacity, and relieve AD [130]. Similarly, 10 weeks of treadmill training was observed to significantly reduce Aβ deposition in the hippocampal tissue of TgAPP/PS1 AD mice and relieve AD symptoms [131]. ...
Alzheimer’s disease (AD), a nervous system disease typically diagnosed in the elderly (aged 65 and above), is characterized by multiple symptoms including progressive memory loss, amnesia, aphasia, agnosia, and visual–spatial dysfunction, eventually leading to death [1]. AD has two typical pathological features: neuroinflammatory plaques formed by the deposition of extracellular amyloid-beta (Aβ) protein in brain tissue; and neurofibrillary tangles (NFTs) formed by the hyperphosphorylation of Tau protein in neurons, eventually manifested as continuous shrinkage of the cortex, and massive loss of neurons in hippocampal and other brain tissues [2]. The etiology and pathogenesis of AD are still unclear. Multiple factors are involved in the occurrence of AD, including Aβ toxicity, abnormal phosphorylation of the Tau protein, neuroinflammation, gene mutation, neurotransmitter loss, oxidative stress, and mitochondrial dysfunction [3]. An increase in the elderly population has also resulted in an increase in the incidents of AD. This trend has prompted new research efforts, including the development of donepezil, galantamine, and memantine, and these drugs can improve the symptoms of patients with moderate and mild AD, but there are currently no therapeutics capable of preventing, stopping, or reversing the development of AD.
... Since there are still no drugs available for this type of disease, physical activity (PA) is the best means of controlling and rehabilitating people with dementia [40,41] because other alternatives such therapies often lead to side effects and changes in the behavior of patients [42]. `Exercising PA can have a positive effect on pathogenic by-products that negatively affect a person's behavior [43,44], also, PA affects the improvement of basic motor functions such as walking, balance, which are otherwise significantly impaired. this disease [45]. ...
The concept of dementia is associated with cognitive changes, behavioral changes, as well as daily motor actions and life functions. The association of physical activity with dementia is a controversial topic in science and is always an interesting basis for discussion among researchers. Moderate PA can be an effective means of reducing the rate of dementia as well as behavioral problems, however caution should be approached when working with this group of people, especially when setting end goals. Given the division of dementia, each person needs to be approached individually and appropriate selection made. The contribution of PA is irreplaceable compared to any type of therapeutic treatment, it improves basic life functions, reduces the mortality rate and improves the quality of life.
(Keywords: Alzheimer's, Exercise, Older people, Brain health, Prevalence, QOL.)
... Since there are still no drugs available for this type of disease, physical activity (PA) is the best means of controlling and rehabilitating people with dementia [40,41] because other alternatives such therapies often lead to side effects and changes in the behavior of patients [42]. `Exercising PA can have a positive effect on pathogenic by-products that negatively affect a person's behavior [43,44], also, PA affects the improvement of basic motor functions such as walking, balance, which are otherwise significantly impaired. this disease [45]. ...
The concept of dementia is associated with cognitive changes, behavioral changes, as well as daily motor actions and life functions. The association of physical activity with dementia is a controversial topic in science and is always an interesting basis for discussion among researchers. Moderate PA can be an effective means of reducing the rate of dementia as well as behavioral problems, however caution should be approached when working with this group of people, especially when setting end goals. Given the division of dementia, each person needs to be approached individually and appropriate selection made. The contribution of PA is irreplaceable compared to any type of therapeutic treatment, it improves basic life functions, reduces the mortality rate and improves the quality of life.
... Neurons and glial cells internalize these proteins into cells through endocytosis and then degrade them using autophagy-lysosome and ubiquitin-proteasome systems, thereby protecting neuronal cells [306]. Exercise activates autophagy in the brain as well as muscles [307], and it has been reported that physical activity not only lowers levels of pathogenic protein aggregation in various ND models [308,309], but also tau in normal brains of the elderly [310]. However, there are insufficient data supporting these findings, and the specific mechanism is also unclear. ...
Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.
... Exercise is one of the most promising treatments for influencing hippocampal volume. In rodents, exercise increases cell proliferation in both younger and older animals, particularly in the dentate gyrus (Cahill et al., 2015;Klein et al., 2017;Van Praag, Kempermann, & Gage, 1999;Yuede et al., 2009), and these effects occur independently of environmental enrichment and social interaction (Van Praag et al., 1999). Exercise may also induce macroscale changes, such as synaptogenesis, altered neuronal morphology, and angiogenesis (Vivar, Potter, & van Praag, 2013) and induce biochemical changes, including upregulation of key neurotrophins and growth factors, such as brain-derived neurotrophic factor (BDNF) and ...
Hippocampal volume is a marker of brain health and is reduced with aging and neurological disease. Exercise may be effective at increasing and preserving hippocampal volume, potentially serving as a treatment for conditions associated with hippocampal atrophy (e.g., dementia). This meta‐analysis aimed to identify whether exercise training has a positive effect on hippocampal volume and how population characteristics and exercise parameters moderate this effect. Studies met the following criteria: (a) controlled trials; (b) interventions of physical exercise; (c) included at least one time‐point of hippocampal volume data before the intervention and one after; (d) assessed hippocampal volume using either manual or automated segmentation algorithms. Animal studies, voxel‐based morphometry analyses, and multi‐modal interventions (e.g., cognitive training or meditation) were excluded. The primary analysis in n = 23 interventions from 22 published studies revealed a significant positive effect of exercise on total hippocampal volume. The overall effect was significant in older samples (65 years of age or older) and in interventions that lasted over 24 weeks and had less than 150 min per week of exercise. These findings suggest that moderate amounts of exercise for interventions greater than 6 months have a positive effect on hippocampal volume including in older populations vulnerable to hippocampal atrophy.
... However, some studies have reported the effect of voluntary exercise alone. It seems that the different outcome is due to the duration of exercise (Nichol, Deeny, Seif, Camaclang, & Cotman, 2009;Yuede et al., 2009), novel object recognition test protocol, age, and gender (Hopkins & Bucci, 2010;Hopkins, Nitecki, & Bucci, 2011). ...
Introduction:
Previous studies demonstrated that forced and voluntary exercise had ameliorative effects on behavioral tasks followed by Sleep Deprivation (SD) in intact female rats. The main goal of this research was evaluating the impact of voluntary exercise on cognitive functions while SD and ovariectomization is induced in female wistar rats.
Methods:
The rats were anesthesized combining dosage of ketamine and xylazine. Then, both ovaries were eliminated and 3 weeks after surgery the animals entered the study. The exercise protocol took 4 weeks of voluntary exercise in a wheel which was connected to home cage. For inducing a 72 hours deprivation the multiple platforms was applied. The cognitive functions were studied by exploiting the Morris Water Maze (MWM) and Novel object recognition tests. Anxiety was evaluated by open field test and corticostrone measurement was carried out by ELISA method. One-way and two-way ANOVA and repeated measures were utilized for data analysis and P<0.05 was considered statistically significant.
Results:
We observed significant spatial and recognition learning and memory impairments in OVX sleep-deprived rats compared to the control group and voluntary exercise alleviated the SD-induced learning and memory defects.
Conclusion:
We concluded that voluntary exercise can improve cognitive impairments followed by SD in OVX female rats.
... 66 Mouse models for AD consistently show an association between physical activity or exercise and preserved cognitive functions. [67][68][69][70] In line with this, exercise increases dendritic arborization, 71 maturation of dendritic spines, 72,73 hippocampal neurogenesis, and reduces the ADrelated loss of spatial memory. 74 Whether exercise also induces neurogenesis in the V-SVZ remains controversial. ...
Aim: Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular-subventricular zone. Neurogenesis in both niches is reduced in aging and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular-subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1 -dependent effects on neurogenesis in the two main neurogenic niches.
Methods: Wildtype and HCA1 knock-out mice received high intensity interval exercise, subcutaneous injections of L-lactate, or saline injections, five days per week for seven weeks. Well-established markers for proliferating cells (Ki-67) and immature neurons (doublecortin), were used to investigate neurogenesis in subgranular zone and ventricular-subventricular zone.
Results: We demonstrated that neurogenesis in the ventricular-subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild type, but not in HCA1 knock-out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment.
Conclusion: Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular-subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age-related cognitive decline.
Keywords: GPR81; HCA1; HCAR1; adult neurogenesis; exercise; lactate.
... Exercise training has been found to either decrease [10][11][12] or not change [13,14] amyloid plaque load. Likewise, brain soluble Aβ (sAβ) levels have been shown to decrease [10,12,15] or not change [16] with exercise training. intervention may be one of the reasons for this contradiction. ...
Alzheimer’s Disease (AD), the most common form of dementia, is characterized by progressive deficits in cognitive function. Amyloid-beta (Aβ) peptides are believed to play a decisive role in the pathology of AD. Improving the clearance of toxic Aβ has, therefore, become a therapeutic strategy for AD. Unfortunately, almost all of the drug candidates tested for AD, including the Aβ centric therapeutic approaches, until now have failed to exhibit any efficacy. Previous evidence suggested that aerobic exercise training contributes to the improvement of cognitive decline and slows down pathogenesis of AD; however, the exact mechanisms for this have not been fully understood. One of the most important beneficial effects of aerobic exercise on AD is modifying Aβ clearance. Accumulating evidence indicates that aerobic exercise not only upregulates the clearance of amyloid plaques and soluble Aβ in the brain but also increases its final removal from the periphery. But there are still many unanswered questions in this regard, including the proper timing of exercise interventions, optimal aerobic exercise mode, intensity, duration, and frequency as well as the possible effect of exercise on potential environmental Aβ-clearing agents, which should be considered in future studies.
... The locomotor activity was used to measure differences in general activity or emotionality between treatment groups. Anxietyrelated behavior was assessed in the EPM similar to previously published methods (Wozniak et al., 2013;Yuede et al., 2009). All behavioral testing was conducted during the light cycle, by a female experimenter blinded to experimental group. ...
TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.
... The capacity of running to reduce hippocampal Aβ plaque pathology in 5-month-old TgCRND8 mice (Maliszewska-Cyna, Xhima and Aubert, 2016) is congruent with other studies reporting that shorter periods of physical exercise may be sufficient to reduce Aβ plaque pathology at relatively early stages of disease progression in the hippocampus (Adlard et al., 2005;Tapia-Rojas et al., 2015;Yuede et al., 2009). Longer periods of exercise-even at later disease stages-could also mitigate Aβ pathology, at least in certain brain regions. ...
Physical activity has been correlated with a reduced risk of cognitive decline, including that associated with vascular dementia, mild cognitive impairment (MCI) and Alzheimer's disease (AD); recent literature suggests this may in part result from benefits to the cerebrovascular network. Using a transgenic (Tg) mouse model of AD, we evaluated the effect of running on cortical and hippocampal vascular morphology, cerebral amyloid angiopathy, amyloid plaque load, and spatial memory. TgCRND8 mice present with progressive amyloid pathology, advancing from the cortex to the hippocampus in a time-dependent manner. We postulated that the characteristic progression of pathology could lead to differential, time-dependent effects of physical activity on vascular morphology in these brain regions at 6 months of age. We used two-photon fluorescent microscopy and 3D vessel tracking to characterize vascular and amyloid pathology in sedentary TgCRND8 mice compared those who have a history of physical activity (unlimited access to a running wheel, from 3 to 6 months of age). In sedentary TgCRND8 mice, capillary density was found to be lower in the cortex and higher in the hippocampus compared to non-transgenic (nonTg) littermates. Capillary length, vessel branching, and non-capillary vessel tortuosity were also higher in the hippocampus of sedentary TgCRND8 compared to nonTg mice. Three months of voluntary running resulted in normalizing cortical and hippocampal microvascular morphology, with no significant difference between TgCRND8 and nonTg mice. The benefits of physical activity on cortical and hippocampal vasculature in 6-month old TgCRND8 mice were not paralleled by significant changes on parenchymal and cerebral amyloid pathology. Short-term spatial memory— as evaluated by performance in the Y-maze— was significantly improved in running compared to sedentary TgCRND8 mice. These results suggest that long-term voluntary running contributes to the maintenance of vascular morphology and spatial memory in TgCRND8 mice, even in the absence of an effect on amyloid pathology.
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is marked by cognitive decline, neuroinflammation, and neuronal loss. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression, influencing key pathways involved in neuroinflammation and neurodegeneration in AD. This review delves into the multifaceted role of exercise in modulating miRNA expression and its interplay with the gut microbiome, proposing a comprehensive framework for neuroprotection in AD. By synthesizing current research, we elucidate how exercise-induced changes in miRNA profiles can mitigate inflammatory responses, promote neurogenesis, and reduce amyloid-beta and tau pathologies. Additionally, we explore the gut–brain axis, highlighting how exercise-driven alterations in gut microbiota composition can further influence miRNA expression, thereby enhancing cognitive function and reducing neuroinflammatory markers. This holistic approach underscores the potential of targeting exercise-regulated miRNAs and gut microbiome interactions as a novel, noninvasive therapeutic strategy to decelerate AD progression and improve quality of life for patients. This approach aims to decelerate disease progression and improve patient outcomes, offering a promising avenue for enhancing the effectiveness of AD management.
Schizophrenia (SCZ) is a profound neurological disorder that affects approximately 1% of the global population. Alpha-pinene (α-pinene) is a natural and active monoterpene found in coniferous tree oil, primarily pine, with diverse pharmacological characteristics, including antioxidative, anxiolytic, and antidepressant properties. This research study delves into the neuroprotective effects of α-pinene on oxidative stress, memory deficits, and depressive and anxiety-like behaviors in a ketamine-induced mice model of SCZ using male mice. The mice were randomly divided into six groups: vehicle, control, positive control, ketamine, α-pinene at 50 mg/kg, and α-pinene at 100 mg/kg. Treatment of the ketamine-induced mice model of SCZ with α-pinene yielded significant improvements in depressive and anxiety-like behaviors and cognitive impairments. Furthermore, it significantly elevated glutathione (GSH) levels, total antioxidant capacity (TAC), dopamine levels, catalase (CAT), and superoxide dismutase (SOD) activities while markedly reducing malondialdehyde (MDA) levels. The current study establishes that α-pinene treatment effectively mitigates oxidative damage, cognitive deficits, and depressive and anxiogenic-like behaviors in the brains of ketamine-treated mice. Therefore, α-pinene treatment is an efficacious approach to forestall the neurobehavioral and neurobiochemical adverse effects of the ketamine-induced SCZ model of mice.
Alzheimer’s disease (AD) is the main neurodegenerative disorder characterized by several pathophysiological features, including the misfolding of the tau protein and the amyloid beta (Aβ) peptide, neuroinflammation, oxidative stress, synaptic dysfunction, metabolic alterations, and cognitive impairment. These mechanisms collectively contribute to neurodegeneration, necessitating the exploration of therapeutic approaches with multiple targets. Physical exercise has emerged as a promising non-pharmacological intervention for AD, with demonstrated effects on promoting neurogenesis, activating neurotrophic factors, reducing Aβ aggregates, minimizing the formation of neurofibrillary tangles (NFTs), dampening inflammatory processes, mitigating oxidative stress, and improving the functionality of the neurovascular unit (NVU). Overall, the neuroprotective effects of exercise are not singular, but are multi-targets. Numerous studies have investigated physical exercise’s potential in both AD patients and animal models, employing various exercise protocols to elucidate the underlying neurobiological mechanisms and effects. The objective of this review is to analyze the neurological therapeutic effects of these exercise protocols in animal models and compare them with studies conducted in AD patients. By translating findings from different approaches, this review aims to identify opportune, specific, and personalized therapeutic windows, thus advancing research on the use of physical exercise with AD patients.
Pathological changes in the medial prefrontal cortex (mPFC) and astrocytes are closely associated with Alzheimer's disease (AD). Voluntary running has been found to effectively delay AD. However, the effects of voluntary running on mPFC astrocytes in AD are unclear. A total of 40 10-month-old male amyloid precursor protein/presenilin 1 (APP/PS1) mice and 40 wild-type (WT) mice were randomly divided into control and running groups, and the running groups underwent voluntary running for 3 months. Mouse cognition was assessed by the novel object recognition (NOR), Morris water maze (MWM), and Y maze tests. The effects of voluntary running on mPFC astrocytes were investigated using immunohistochemistry, immunofluorescence, western blotting, and stereology. APP/PS1 mice performed significantly worse than WT mice in the NOR, MWM, and Y maze tests, and voluntary running improved the performance of APP/PS1 mice in these tests. The total number of mPFC astrocytes was increased, cell bodies were enlarged, and protrusion number and length were increased in AD mice compared with WT mice, but there was no difference in component 3 (C3) levels in the mPFC (total mPFC level); however, C3 and S100B levels in astrocytes were increased in AD mice. Voluntary running reduced the total number of astrocytes and S100B levels in astrocytes and increased the density of PSD95+ puncta in direct contact with astrocyte protrusions in the APP/PS1 mouse mPFC. Three months of voluntary running inhibited astrocyte hyperplasia and S100B expression in astrocytes, increased the density of synapses in contact with astrocytes, and improved cognitive function in APP/PS1 mice.
Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease (AD). Adult hippocampal neurogenesis (AHN) is reduced in AD patients. Exercise stimulates AHN in rodents and improves memory and slows cognitive decline in AD patients. However, the molecular pathways for exercise-induced AHN and improved cognition in AD are poorly understood. Here, we show that voluntary running in APP SWE mice restores their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus (DG) neuronal progenitors (NPs), which also abolished running-mediated increases in AHN. AHN was reduced in sedentary APP SWE mice versus control mice, with basal AHN reduced by RGS6 deletion in DG NPs. RGS6 expression is significantly lower in the DG of AD patients. Thus, RGS6 mediates exercise-induced rescue of impaired cognition and AHN in AD mice, identifying RGS6 in DG NPs as a potential target to combat hippocampal neuron loss in AD.
Teaser
RGS6 expression in hippocampal NPCs promotes voluntary running-induced neurogenesis and restored cognition in APP SWE mice.
Field Codes
RGS6, Alzheimer’s disease, adult hippocampal neurogenesis, neural precursor cells, dentate gyrus, exercise, learning/memory
Alzheimer's disease (AD) is closely related to hippocampal synapse loss, which can be alleviated by running exercise. However, further studies are needed to determine whether running exercise reduces synapse loss in the hippocampus in an AD model by regulating microglia. Ten-month-old male wild-type mice and APP/PS1 mice were randomly divided into control and running groups. All mice in the running groups were subjected to voluntary running exercise for four months. After the behavioral tests, immunohistochemistry, stereological methods, immunofluorescence staining, 3D reconstruction, western blotting and RNA-Seq were performed. Running exercise improved the spatial learning and memory abilities of APP/PS1 mice and increased the total number of dendritic spines, the levels of the PSD-95 and Synapsin Ia/b proteins, the colocalization of PSD-95 and neuronal dendrites (MAP-2) and the number of PSD-95-contacting astrocytes (GFAP) in the hippocampi of APP/PS1 mice. Moreover, running exercise reduced the relative expression of CD68 and Iba-1, the number of Iba-1+ microglia and the colocalization of PSD-95 and Iba-1+ microglia in the hippocampi of APP/PS1 mice. The RNA-Seq results showed that some differentially expressed genes (DEGs) related to the complement system (Cd59b, Serping1, Cfh, A2m, and Trem2) were upregulated in the hippocampi of APP/PS1 mice, while running exercise downregulated the C3 gene. At the protein level, running exercise also reduced the expression of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), C1q and C3 in the hippocampus and AGEs and RAGE in hippocampal microglia in APP/PS1 mice. Furthermore, the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes were upregulated in the hippocampi of APP/PS1 mice but downregulated after running, and these genes were associated with the C3 and RAGE genes according to protein-protein interaction (PPI) analysis. These findings indicate that long-term voluntary exercise might protect hippocampal synapses and affect the function and activation of microglia, the AGE/RAGE signaling pathway in microglia and the C1q/C3 complement system in the hippocampus in APP/PS1 mice, and these effects may be related to the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes. The current results provide an important basis for identifying targets for the prevention and treatment of AD.
Although liver is rich in peroxisome proliferator-activated receptor α (PPARα), recently we have described the presence of PPARα in hippocampus where it is involved in non-amyloidogenic metabolism of amyloid precursor protein (APP) via ADAM10, decreasing amyloid plaques and improving memory and learning. However, mechanisms to upregulate PPARα in vivo in the hippocampus are poorly understood. Regular exercise has multiple beneficial effects on human health and here, we describe the importance of regular mild treadmill exercise in upregulating PPARα in vivo in the hippocampus of 5XFAD mouse model of Alzheimer's disease. We also demonstrate that treadmill exercise remained unable to stimulate ADAM10, reduce plaque pathology and improve cognitive functions in 5XFADΔPPARα mice (5XFAD mice lacking PPARα). On the other hand, treadmill workout increased ADAM10, decreased plaque pathology and protected memory and learning in 5XFADΔPPARβ mice (5XFAD mice lacking PPARβ). Moreover, the other PPAR (PPARγ) also did not play any role in the transcription of ADAM10 in vivo in the hippocampus of treadmill exercised 5XFAD mice. These results underline an important role of PPARα in which treadmill exercise remains unable to exhibit neuroprotection in the hippocampus in the absence of PPARα.
Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive function; however, recent evidence suggests that non-cognitive sensorimotor and psychomotor symptoms accompany early stages of the disease in humans and AD models. Although exercise is emerging as an important therapeutic to combat AD progression, little is known about the effect of exercise on sensorimotor domain functions. The purpose of this study was to determine if early sensorimotor symptoms accompany deficits in Morris water maze (MWM) performance in the 3xTg-AD model, and investigate if exercise could protect against early behavioral decline. 3xTg-AD and wild-type (WT) control mice were subjected to 12 weeks of moderate intensity wheel running or remained sedentary. At 6 months of age, animals underwent a series of sensorimotor and MWM testing. 3xTg-AD mice displayed deficits in sensorimotor function (beam traversal, spontaneous activity, and adhesive removal) and MWM performance. Interestingly, 3xTg-AD animals exhibited increased freezing and unusual shaking/tremoring behaviors not displayed by WT controls. Exercise improved beam traversal, adhesive removal, and reduced the unusual motor-related behaviors in 3xTg-AD mice. Our study shows that sensorimotor symptoms coincide with deficits in MWM performance, and suggest that exercise may mitigate deficits associated with early disease in 3xTg-AD mice.
The benefits of exercise to human health have long been recognised. However only in the past decade have researchers started to discover the molecular benefits that exercise confers, especially to the central nervous system. These discoveries include the magnitude of molecular messages that are communicated from skeletal muscle to the central nervous system. Despite these advances in understanding, very limited studies have been conducted to decipher the molecular benefits of exercise in retinal health and disease. Here, we review the latest work on the effects of exercise on the retina and discuss its effects on the wider central nervous system, with a focus on demonstrating the potential applicability and comparative molecular mechanisms that may be occurring in the retina. This review covers the key molecular pathways where exercise exerts its effects: oxidative stress and mitochondrial health; inflammation; protein aggregation; neuronal health; and tissue crosstalk via extracellular vesicles. Further research on the benefits of exercise to the retina and its molecular messages within extracellular vesicles is highly topical in this field of research.
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Mild traumatic brain injury (mTBI) accounts for a large majority of traumatic brain injuries sustained globally each year. Older adults, who are already susceptible to age-related declines to neurocognitive health, appear to be at an increased risk of both sustaining an mTBI and experiencing slower or impaired recovery. There is also growing evidence that mTBI is a potential risk factor for accelerated cognitive decline and neurodegeneration. Lifestyle-based interventions are gaining prominence as a cost-effective means of maintaining cognitive health with age. Consequently, inter-individual variations in exercise, sleep, and dietary patterns post-mTBI could influence the trajectory of neurocognitive recovery, particularly in older adults. This review synthesises the current animal and human literature centred on the mechanisms through which lifestyle modifications are thought to influence acute and longer-term cognitive functioning and brain health following mTBI. Numerous lifestyle-driven neuroprotective processes have been established in animal models of TBI. However, the literature is characterised by a lack of translation to human samples and limited appraisal of the interaction between ageing and brain injury. Further research is needed to better establish the therapeutic utility of applying lifestyle-based interventions to older adults with a recent history of mTBI.
To determine whether voluntary wheel running could improve cognitive function from both the young and middle-aged APP/PS1 mice and the underlying mechanisms involved in. Young (9-weeks old) and middle-aged (24-weeks old) APP/PS1 mice were randomly assigned into control and exercise groups, respectively. Mice from exercise group had free and unlimited access to the running wheel for a total of 16 weeks. Voluntary exercise only improved cognitive function from young but not the middle-aged APP/PS1 mice. This might be owing to that in young APP/PS1 mice voluntary exercise reduced tau phosphorylation via inhibiting p-GSK3β activity, as well as reduced neuro-inflammation and elevated key proteins involved in synaptic plasticity. Additionally, exercise also elevated circulating L-Valine, Glucosamine, Formylanthranilic acid, Myristic acid level and improved gut microbiota profiles (i.e. elevated Oscillibacter, EF097061_g, EU454870_g, EU504554_g, EU505046_g and EF096172_g and reduced Alistipes). Improved circulating metabolites and intestinal microbiome might also contribute to improved learning and memory abilities post exercise. For the middle-aged APP/PS1 mice, exercise reduced ADAM10 and GFAP protein expression in hippocampus, with no notable alterations in circulating metabolites; additionally, mice from exercise group had markedly reduced abundance of the phyla Proteobacteria and Tenericutes, genera Bacteroides and Faecalibacterium, and elevated abundance of the genera Allobaculum. It is suggested that voluntary exercise should be initiated at an early adulthood period rather than at late stage in order to prevent cognitive decline or Alzheimer’s disease.
Epidemiological studies suggest that physical exercise or cognitive stimulation might contribute to lower the risk of developing dementia disorders such as Alzheimer's disease (AD). Here, we used the well-established enrichment environment (EE) paradigm to study the impact of prolonged physical activity and cognitive stimulation in a mouse model of AD overexpressing only Aβ(4-42) peptides. These mice display age-dependent memory and motor deficits, in the absence of human amyloid precursor protein (APP) overexpression. We demonstrate that housing under EE conditions leads to an entire preservation of recognition and spatial memory, as well as a rescue of motor deficits in this mouse model. Moreover, we find that Tg4-42(hom) mice present a typical floating phenotype in the Morris water maze task that could be completely ameliorated upon long-term EE housing. Our findings are in line with epidemiological studies suggesting that physical activity and cognitive stimulation might represent efficient strategies to prevent age-related neurodegenerative disorders such as AD.
Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer’s disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer’s patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer’s disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of ~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer’s related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer’s disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer’s disease pathology by showing that capillary stalling is not decreased following exercise.
Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
Reviews research on psychomotor slowing in aged and brain-damaged Ss and attempts to identify brain mechanisms related to this slowing. Behavioral, neuroanatomical, and neurophysiological evidence indicate that the basal ganglia with their complex neural connections are importantly involved in the speed of initiating and executing movements. It is suggested that damage or dysfunction of the basal ganglia may be a basis for the psychomotor slowness observed in human and animal Ss. (174 ref.) (PsycINFO Database Record (c) 2006 APA, all rights reserved).
To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life.
Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically.
Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area.
Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age.
Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease.
Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density.
Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life.
Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a
Lys670 → Asn, Met671 → Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment
by 9 to 10 months of age. A fivefold increase in Aβ(1–40) and a 14-fold increase in Aβ(1–42/43) accompanied the appearance
of these behavioral deficits. Numerous Aβ plaques that stained with Congo red dye were present in cortical and limbic structures
of mice with elevated amounts of Aβ. The correlative appearance of behavioral, biochemical, and pathological abnormalities
reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and
neurobiology of this disease.
To examine the age specific risk of Alzheimer's disease according to sex, and to explore the role of education in a cohort of elderly community residents aged 65 years and older.
A community based cohort of elderly people was studied longitudinally for 5 years for the development of dementia. Dementia diagnoses were made according to the DSM III R criteria and Alzheimer's disease was assessed using the NINCDS-ADRDA criteria. Among the 3675 non-demented subjects initially included in the cohort, 2881 participated in the follow up. Hazard ratios of dementia were estimated using a Cox model with delayed entry in which the time scale is the age of the subjects.
During the 5 year follow up, 190 incident cases of dementia, including 140 cases of Alzheimer's disease were identified. The incidence rates of Alzheimer's disease were 0.8/100 person-years in men and 1.4/100 person-years in women. However, the incidence was higher in men than in women before the age of 80 and higher in women than in men after this age. A significant interaction between sex and age was found. The hazard ratio of Alzheimer's disease in women compared with men was estimated to be 0.8 at 75 years and 1.7 at 85 years. The risks of dementia and Alzheimer's disease were associated with a lower educational attainment (hazard ratio=1.8, p<0.001). The increased risk of Alzheimer's disease in women was not changed after adjustment for education.
Women have a higher risk of developing dementia after the age of 80 than men. Low educational attainment is associated with a higher risk of Alzheimer's disease. However, the increased risk in women is not explained by a lower educational level.
Studies in animals showed that stress results in damage to the hippocampus, a brain area involved in learning and memory, with associated memory deficits. The mechanism involves glucocorticoids and possibly serotonin acting through excitatory amino acids to mediate hippocampal atrophy. Patients with posttraumatic stress disorder (PTSD) from Vietnam combat and childhood abuse had deficits on neuropsychological measures that have been validated as probes of hippocampal function. In addition, magnetic resonance imaging (MRI) showed reduction in volume of the hippocampus in both combat veterans and victims of childhood abuse. In combat veterans, hippocampal volume reduction was correlated with deficits in verbal memory on neuropsychological testing. These studies introduce the possibility that experiences in the form of traumatic stressors can have long-term effects on the structure and function of the brain.
The hippocampus is a target of stress hormones, and it is an especially plastic and vulnerable region of the brain. It also responds to gonadal, thyroid, and adrenal hormones, which modulate changes in synapse formation and dendritic structure and regulate dentate gyrus volume during development and in adult life. Two forms of structural plasticity are affected by stress: Repeated stress causes atrophy of dendrites in the CA3 region, and both acute and chronic stress suppresses neurogenesis of dentate gyrus granule neurons. Besides glucocorticoids, excitatory amino acids and N-methyl-D-aspartate (NMDA) receptors are involved in these two forms of plasticity as well as in neuronal death that is caused in pyramidal neurons by seizures and by ischemia. The two forms of hippocampal structural plasticity are relevant to the human hippocampus, which undergoes a selective atrophy in a number of disorders, accompanied by deficits in declarative episodic, spatial, and contextual memory performance. It is important, from a therapeutic standpoint, to distinguish between a permanent loss of cells and a reversible atrophy.
Previous observational and interventional studies have suggested that regular physical exercise may be associated with reduced symptoms of depression. However, the extent to which exercise training may reduce depressive symptoms in older patients with major depressive disorder (MDD) has not been systematically evaluated.
To assess the effectiveness of an aerobic exercise program compared with standard medication (ie, antidepressants) for treatment of MDD in older patients, we conducted a 16-week randomized controlled trial.
One hundred fifty-six men and women with MDD (age, > or = 50 years) were assigned randomly to a program of aerobic exercise, antidepressants (sertraline hydrochloride), or combined exercise and medication. Subjects underwent comprehensive evaluations of depression, including the presence and severity of MDD using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) scores before and after treatment. Secondary outcome measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions.
After 16 weeks of treatment, the groups did not differ statistically on HAM-D or BDI scores (P = .67); adjustment for baseline levels of depression yielded an essentially identical result. Growth curve models revealed that all groups exhibited statistically and clinically significant reductions on HAM-D and BDI scores. However, patients receiving medication alone exhibited the fastest initial response; among patients receiving combination therapy, those with less severe depressive symptoms initially showed a more rapid response than those with initially more severe depressive symptoms.
An exercise training program may be considered an alternative to antidepressants for treatment of depression in older persons. Although antidepressants may facilitate a more rapid initial therapeutic response than exercise, after 16 weeks of treatment exercise was equally effective in reducing depression among patients with MDD.
Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.
The accumulation of amyloid beta protein (Abeta) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry. Changes in Abeta begin at 6-7 months as SDS-insoluble forms of Abeta42 and Abeta40 that require formic acid for solubilization appear. From 6 to 10 months, these insoluble forms increase exponentially. As insoluble Abeta appears, SDS-soluble Abeta decreases slightly, suggesting that it may be converting to an insoluble form. Our data indicate that it is full-length unmodified Abeta that accumulates initially in Tg2576 brain. SDS-resistant Abeta oligomers and most Abeta species that are N-terminally truncated or modified develop only in older Tg2576 mice, in which they are present at levels far lower than in human AD brain. Between 6 and 10 months, when SDS-insoluble Abeta42 and Abeta40 are easily detected in every animal, histopathology is minimal because only isolated Abeta cores can be identified. By 12 months, diffuse plaques are evident. From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted Abeta42 and Abeta40 increase to levels like those observed in AD brains. Coincident with the marked deposition of Abeta in brain, there is a decrease in CSF Abeta and a substantial, highly significant decrease in plasma Abeta. If a similar decline occurs in human plasma, it is possible that measurement of plasma Abeta may be useful as a premorbid biomarker for AD.
Dementia is common, costly, and highly age related. Little attention has been paid to the identification of modifiable lifestyle habits for its prevention.
To explore the association between physical activity and the risk of cognitive impairment and dementia.
Data come from a community sample of 9008 randomly selected men and women 65 years or older, who were evaluated in the 1991-1992 Canadian Study of Health and Aging, a prospective cohort study of dementia. Of the 6434 eligible subjects who were cognitively normal at baseline, 4615 completed a 5-year follow-up. Screening and clinical evaluations were done at both waves of the study. In 1996-1997, 3894 remained without cognitive impairment, 436 were diagnosed as having cognitive impairment-no dementia, and 285 were diagnosed as having dementia.
Incident cognitive impairment and dementia by levels of physical activity at baseline.
Compared with no exercise, physical activity was associated with lower risks of cognitive impairment, Alzheimer disease, and dementia of any type. Significant trends for increased protection with greater physical activity were observed. High levels of physical activity were associated with reduced risks of cognitive impairment (age-, sex-, and education-adjusted odds ratio, 0.58; 95% confidence interval, 0.41-0.83), Alzheimer disease (odds ratio, 0.50; 95% confidence interval, 0.28-0.90), and dementia of any type (odds ratio, 0.63; 95% confidence interval, 0.40-0.98).
Regular physical activity could represent an important and potent protective factor for cognitive decline and dementia in elderly persons.
Oxidative stress is a key feature in the Alzheimer's disease (AD) brain and manifests as lipid peroxidation (LPO). Isoprostanes (iPs) are specific and sensitive markers of in vivo LPO. To determine whether amyloid beta (Abeta) deposition in vivo is associated with increased LPO, we examined iP levels in a transgenic mouse model (Tg2576) of AD amyloidosis. Urine, plasma, and brain tissues were collected from Tg2576 and littermate wild-type (WT) animals at different time points starting at 4 months of age and continuing until 18 months of age. Levels of urinary 8,12-iso-iPF(2alpha)-VI were higher in Tg2576 than in WT animals as early as 8 months of age and remained this high for the rest of the study. A similar pattern was observed for plasma levels of 8,12-iso-iPF(2alpha)-VI. Homogenates from the cerebral cortex and hippocampus of Tg2576 mice had higher levels of 8,12-iso-iPF(2alpha)-VI than those from WT mice starting at 8 months of age. In contrast, a surge of Abeta 1-40 and 1-42 levels as well as Abeta deposits in Tg2576 mouse brains occurred later, at 12 months of age. A direct correlation was observed between brain 8,12-iso-iPF(2alpha)-VI and Abeta 1-40 and 1-42. Because LPO precedes amyloid plaque formation in Tg2576 mice, this suggests that brain oxidative damage contributes to AD pathogenesis before Abeta accumulation in the AD brain.
Transgenic mice expressing mutant amyloid precursor proteins (APPs) have provided important new information about the pathogenesis of Alzheimer's disease (AD) histopathology. However, the molecular basis of memory loss in these mice is poorly understood. One of the major impediments has been the difficulty of distinguishing between age-dependent and age-independent behavioral changes. To address this issue we studied in parallel two lines of APP transgenic mice expressing comparable levels of mutant and wild-type human APP. This enabled us to identify age-independent behavioral deficits that were not specifically related to mutant APP expression. When mice with age-independent deficits were eliminated, we detected memory loss in transgenic mice expressing mutant APP (Tg2576 mice) starting at approximately 6 months, which coincided with the appearance of detergent-insoluble Abeta aggregates (Abeta(insol)). Genetically accelerating the formation of Abeta(insol) resulted in an earlier onset of memory decline. A facile interpretation of these results, namely that memory loss and Abeta(insol) were closely connected, was rejected when we extended our analysis to include older mice. No obvious correspondence between memory and Abeta(insol) was apparent in a combined group of old and young mice unless the mice were stratified by age, whereupon inverse correlations between memory and Abeta(insol) became evident. These results suggested that Abeta(insol) is a surrogate marker for small assemblies of Abeta that disrupt cognition and occur as intermediates during Abeta(insol) formation, and they are the first descriptive in vivo data supporting their role in impairing memory. These studies also provide a methodological framework within which to investigate these Abeta assemblies in vivo.
Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
In the first century, ce, the Roman satirist Juneval famously observed Orandum est, ut sit mens sana in corpore sano, or "A sound mind in a sound body is something to be prayed for." This implicit link between mental and physical health, also paralleled by Eastern philosophies and practices such as tai chi, has survived the millennia since Juneval and his contemporaries. More recently, controlled examinations of the effects of physical fitness on cognitive performance have shown that improving cardiovascular fitness (CVF) can help to reduce the deleterious effects of age on cognition and brain structure. Thus, as we age, it may well be the case that a sound mind is a natural concomitant of a sound body. Numerous cross-sectional and longitudinal studies have examined the effects of aerobic exercise on cognitive performance in aging humans since earlier studies, which found that physically fit older adults performed better on simple cognitive tasks than their less-fit counterparts. This base of knowledge recently has been furthered through examinations of cortical structure (Colcombe et al., 2003) and neurocognitive function in aging humans via functional and structural magnetic resonance imaging techniques. In this manuscript, we will briefly review some of our recent research on the effects of CVF on brain function, structure, and behavior in older adults. We will then outline some of our current and future directions in this area.
Background
An increasing body of evidence implicates both brain inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). The relevance of their interaction in vivo, however, is unknown. Previously, we have shown that separate pharmacological targeting of these two components results in amelioration of the amyloidogenic phenotype of a transgenic mouse model of AD-like brain amyloidosis (Tg2576).
Methods
In the present study, we investigated the therapeutic effects of a combination of an anti-inflammatory agent, indomethacin, and a natural anti-oxidant, vitamin E, in the Tg2576 mice. For this reason, animals were treated continuously from 8 (prior to Aβ deposition) through 15 (when Aβ deposits are abundant) months of age.
Results
At the end of the study, these therapeutic interventions suppressed brain inflammatory and oxidative stress responses in the mice. This effect was accompanied by significant reductions of soluble and insoluble Aβ1-40 and Aβ1-42 in neocortex and hippocampus, wherein the burden of Aβ deposits also was significantly decreased.
Conclusions
The results of the present study support the concept that brain oxidative stress and inflammation coexist in this animal model of AD-like brain amyloidosis, but they represent two distinct therapeutic targets in the disease pathogenesis. We propose that a combination of anti-inflammatory and anti-oxidant drugs may be a useful strategy for treating AD.
Background:
Chronic stress is associated with hippocampal damage and impaired memory in animals and humans.
Objective:
To examine this relationship with clinical and pathologic data from the Religious Orders Study.
Methods:
Older Catholic clergy members underwent annual clinical evaluations, which included clinical classification of Alzheimer's disease (AD) and detailed cognitive function testing from which composite measures of global cognition and specific cognitive functions were derived. At the baseline evaluation, participants completed a measure of the tendency to experience psychological distress, a stable personality trait that served as an indicator of susceptibility to negative emotional states across the life span. More than 90% of participants who died underwent a uniform postmortem examination of the brain from which summary measures of AD pathology were derived. The association of distress proneness with incident AD and cognitive decline and with measures of AD pathology was examined in analyses adjusted for selected demographic and clinical variables.
Results:
During a mean of 4.9 years of follow-up, 140 persons developed AD. Those high in distress proneness (90th percentile) had twice the risk of developing AD than those low in distress proneness (10th percentile). Distress proneness was related to decline in episodic memory but not in other cognitive domains, with a >10-fold increase in episodic memory decline in those high in distress proneness compared with those low in the trait. Among those who died, however, distress proneness was not related to common measures of AD pathology.
Conclusion:
Proneness to experience psychological distress is a risk factor for AD, an effect independent of AD pathologic markers such as cortical plaques and tangles.
In this study, the authors evaluated whether the association between low educational level and increased risk of Alzheimer's disease (AD) and dementia may be explained by occupation-based socioeconomic status (SES). A cohort of 931 nondemented subjects aged ≥75 years from the Kungsholmen Project, Stockholm, Sweden, was followed for 3 years between 1987 and 1993. A total of 101 incident cases of dementia, 76 involving AD, were detected. Less-educated subjects had an adjusted relative risk of developing AD of 3.4 (95% confidence interval: 2.0, 6.0), and subjects with lower SES had an adjusted relative risk of 1.6 (95% confidence interval: 1.0, 2.5). When both education and SES were introduced into the same model, only education remained significantly associated with AD. Combinations of low education with low or high SES were associated with similar increased risks of AD, but well-educated subjects with low SES were not at high risk. Low SES at 20 years of age, even when SES was high at age 40 or 60 years, was associated with increased risk; however, this increase disappeared when education was entered into the model. In conclusion, the association between low education and increased AD risk was not mediated by adult SES or socioeconomic mobility. This suggests that early life factors may be relevant.
Objective.
—To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life.Design.
—Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically.Setting.
—Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area.Participants.
—Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age.Main Outcome Measures.
—Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease.Results.
—Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density.Conclusions.
—Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life.(JAMA. 1996;275:528-532)
A common analogy to aging is that of a boulder being worn down to rubble by the unremitting onslaught of time. In contrast, Swaab's "use it or lose it" concept is important because it emphasizes some positive consequences of experience. For example, early exposure to complex experience may offer some protection from "wear and tear" degradation through improvements in vascular support, diet, exercise, and coping with stress. Exposure to complex experience in old age can also generate new synapses in the cerebral cortex and cerebellum. This new perspective is not completely positive, however, because it appears that the senescent breakdown of supporting systems may ultimately constrain the positive benefits of experience in old age. Thus the evidence indicates that the use of environmental therapies should encompass the entire life span to produce successful aging.
This chapter reviews the present knowledge concerning the cell biology of how glucocorticoids (GCs) damage hippocampal neurons. It presents studies that suggest that GCs leave hippocampal neurons in a state of metabolic vulnerability. In the absence of a coincident metabolic challenge, this vulnerability is survived readily. However, when co-incident insults occur, neuronal viability is compromised, at least in part via exacerbation of the EAA cascade of damage. These observations are of some potential relevance, in that they suggest that exogenous GCs, in the aftermath of some insults, can potentially exacerbate hippocampal damage, and should be avoided if possible. It has been shown that inhibiting the GC stress response in the aftermath of status epilepticus seizures, by administering the adrenal steroidogenesis inhibitor metyrapone, diminish hippocampal damage. In an approach meant to decrease the total lifetime exposure to GCs, the chapter demonstrates that a neonatal behavioral intervention that reduces adult basal GC concentrations in the rat prevents some neuron loss and spatial learning deficits that characterize aging in the rat.
Glucocorticoids, the adrenocortical hormones secreted during stress, can be cumulatively toxic to hippocampal neurons, and this steroid-induced neuron loss has a role in functional impairments of the senescent hippocampus. The glucocorticoids, through their varied catabolic actions, appear to non-specifically induce metabolic vulnerability in the hippocampal neurons. As such, a wide variety of unrelated toxic insults which damage the hippocampus have their toxicity exacerbated by glucocorticoid treatment and attenuated by adrenalectomy. The present report demonstrates such a synergy between corticosterone (CORT), the species-specific glucocorticoid of rats, and 3-acetylpyridine (3-AP), a neurotoxic antimetabolite which inhibits ATP synthesis. When microinfused into Ammon's horn, 3-AP destroys dentate gyrus neurons preferentially. Administration of CORT at a concentration producing titers equivalent to those seen after prolonged stress, prior to and following 3-AP infusion, caused a 5-fold increase in the volume of hippocampal damage induced by the toxin. Conversely, adrenalectomy prior to microinfusion reduced the toxin's potency by more than 60%. Both the history of elevated CORT (i.e. prior to the 3-AP infusion) and the elevated CORT titers in the aftermath of the infusion contributed to the exaggerated damage. Finally, as little as 24 h of elevated CORT prior to and following the microinfusion could significantly potentiate toxin-induced damage. These studies present further evidence for CORT compromising the capacity of hippocampal neurons to survive a variety of toxic insults. Furthermore, the time-course of this effect suggests the relatively rapid metabolic actions of CORT as critical to this endangerment.
Data suggest, but fall short of proving, that an increase in habitual physical activity is beneficial. Likely benefits may be as much or more in the area of an improved quality of life as in life extension-quantity. If levels of acceptance of preventive regimens can be categorized as the possible, the prudent, and the proved, there appears sufficient reason to place physical activity as being among the prudent actions to be recommended at present. More studies are urgently needed, particularly concerning whether increased physical activity will contribute to cardiovascular and general health enhancement, increased total human performance and a vigorous creative society.While studies develop better definition, it seems possible with exercise stress testing to “clear” individuals relative to the intensity of exertion that involves an acceptably low hazard of acute cardiac catastrophe yet will provide a predictable improvement in physiologic capability. It appears possible to prescribe the intensity of activity from recently developed information concerning heart rate responses. It is possible also to make useful recommendations as to the type, frequency, and duration of various activities on an individual basis that will fit in with the interests and desired life style of individuals.
Stress affects cognition in a number of ways, acting rapidly via catecholamines and more slowly via glucocorticoids. Catecholamine actions involve beta adrenergic receptors and also availability of glucose, whereas glucocorticoids biphasically modulate synaptic plasticity over hours and also produce longer-term changes in dendritic structure that last for weeks. Prolonged exposure to stress leads to loss of neurons, particularly in the hippocampus. Recent evidence suggests that the glucocorticoid- and stress-related cognitive impairments involving declarative memory are probably related to the changes they effect in the hippocampus, whereas the stress-induced catecholamine effects on emotionally laden memories are postulated to involve structures such as the amgydala.
Preischemic spontaneous locomotor activity was distinguished in this laboratory as a factor influencing outcome after 15 and 20 minutes of forebrain ischemia in gerbils. Histological investigations were carried out to analyze potential relations between postischemic survival and a reduction of cerebral damage by spontaneous locomotor activity.
Male Mongolian gerbils were divided into two groups, one with access to running wheels ("runners") and one kept in conventional cages ("nonrunners") for 2 weeks preceding forebrain ischemia of 15 or 20 minutes. A total of 99 gerbils were divided in subgroups and were allowed to recover for 2 weeks for assessment of survival. Other subgroups (n = 7 to 9) were killed at day 4 for quantitative histology of selectively vulnerable areas such as hippocampus, cortex, striatum, and thalamus.
Two weeks after 15-minute ischemia, 44% of non-runners had survived compared with 90% of runners (P < .01). With 20-minute ischemia all runners survived compared with 21% of nonrunners. Quantitative histology (15-minute ischemia) revealed selective nerve cell injury in various cerebral regions in both groups. In runners, however, with the exception of the CA1 sector, damage was attenuated in cortex, striatum, and hippocampus. Furthermore, the extent of thalamic infarction was reduced (P < .05).
Locomotor activity before global cerebral ischemia is highly efficient in protecting the brain as demonstrated by enhanced survival and a reduction of tissue damage in Mongolian gerbils. The mechanisms underlying this protection are currently unclear. However, further understanding of this intriguing phenomenon should enhance the understanding of ischemia pathophysiology and lead to the development of new treatment strategies.
This paper summarizes our studies examining whether changes in levels of brain monoamines after chronic exercise are associated with altered behavioral and endocrine responses to stressors other than exercise. The focus is on using animal models relevant for understanding reports by humans that regular physical activity reduces depression and anxiety. We studied the effects of chronic activity wheel running or treadmill exercise training on levels of norepinephrine (NE) measured in brain cell bodies and terminal regions at rest and after behavioral stress. We also measured brain levels of serotonin, i.e., 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma aminobutyric acid (GABA), which function as both antagonists and synergists with NE. In general, we found that chronic activity wheel running increased NE levels in the pons medulla at rest and protected against NE depletion in locus coeruleus cell bodies after footshock; the concomitant reduction in escape-latency was consistent with an antidepressant effect. Wheel running also decreased the density of GABAA receptors in the corpus striatum while increasing open-field locomotion, consistent with an anxiolytic effect, but had no effect on hypothalamic-pituitary-adrenal cortical response to footshock measured by plasma levels of adrenocorticotropic hormone (ACTH), corticosterone, and prolactin. In contrast, treadmill exercise training increased the metabolism of NE in brain ascending terminal areas for NE, increased the secretion of ACTH after footshock and immobilization stress and had no effect on GABAA receptor density or open field locomotion. The validity of animal models for studying depression and anxiety after forced versus voluntary exercise is discussed. Recommendations are offered for improving the methods used in this area of research.
Previous research has yielded inconsistent results on the effects of exercise, smoking and alcohol use on cognitive impairment and dementia in old age. We analysed data from the Sydney Older Persons Study to see if these health habits were associated with cognitive functioning, dementia or Alzheimer's disease. Health habits were assessed in Wave 1 of the study, when the subjects were aged 75 years or over. Three years later, the subjects were tested for cognitive functioning and clinically examined for dementia and Alzheimer's disease. The analysis was restricted to the 327 subjects examined in Wave 2 who were non-demented in Wave 1. There were few significant associations between health habits and cognitive performance and these were not found consistently across cognitive measures. No associations were found with dementia or Alzheimer's disease. While these health habits do not affect risk for dementia and cognitive impairment in the very elderly, who are at highest risk for these disorders, we cannot discount a role at younger ages.
Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.
The association between antecedent head injury and AD is inconsistent.
To examine the association between early adult head injury, as documented by military hospital records, and dementia in late life; and to evaluate the interaction between head injury and APOE epsilon4 as risk factors for dementia.
The study had a population-based prospective historical cohort design. It included men who were World War II Navy and Marine veterans, and were hospitalized during their military service with a diagnosis of either a nonpenetrating head injury or another unrelated condition. In 1996 to 1997, military medical records were abstracted to document the occurrence and details of closed head injury. The entire sample was then evaluated for dementia and AD using a multistage procedure. There were 548 veterans with head injury and 1228 without head injury who completed all assigned stages of the study. The authors estimated risk of dementia, specifically AD, using proportional hazards models.
Both moderate head injury (hazard ratio [HR] = 2.32; CI = 1.04 to 5.17) and severe head injury (HR = 4.51; CI = 1.77 to 11.47) were associated with increased risk of AD. Results were similar for dementia in general. The results for mild head injury were inconclusive. When the authors stratified by the number of APOE epsilon4 alleles, they observed a nonsignificant trend toward a stronger association between AD and head injury in men with more epsilon4 alleles.
Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life. However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.
The hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive effects in the short run and yet can accelerate pathophysiology when they are over-produced or mismanaged. Here we consider the protective and damaging effects of these mediators as they relate to the immune system and brain. 'Stress' is a principle focus, but this term is rather imprecise. Therefore, the article begins by noting two new terms, allostasis and allostatic load that are intended to supplement and clarify the meanings of 'stress' and 'homeostasis'. For the immune system, acute stress enhances immune function whereas chronic stress suppresses it. These effects can be beneficial for some types of immune responses and deleterious for others. A key mechanism involves the stress-hormone dependent translocation of immune cells in the blood to tissues and organs where an immune defense is needed. For the brain, acute stress enhances the memory of events that are potentially threatening to the organism. Chronic stress, on the other hand, causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as well as functional changes, involving the suppression of ongoing neurogenesis in the dentate gyrus and remodelling of dendrites in the Ammon's horn. Under extreme conditions only does permanent damage ensue. Adrenal steroids tell only part of the story as far as how the brain adapts, or shows damage, and local tissue modulators - cytokines for the immune response and excitatory amino acid neurotransmitters for the hippocampus. Moreover, comparison of the effects of experimenter-applied stressors and psychosocial stressors show that what animals do to each other is often more potent than what experimenters do to them. And yet, even then, the brain is resilient and capable of adaptive plasticity. Stress-induced structural changes in brain regions such as the hippocampus have clinical ramifications for disorders such as depression, post-traumatic stress disorder and individual differences in the aging process.
The importance of maintaining physical fitness by engaging in exercise in a life-long perspective as well as the avoidance of obesity has been emphasised in recent years by epidemiological studies on human populations as well as studies on laboratory rodents. In laboratory studies, voluntary running in wheels and forced training in a treadmill have been used with beneficial results. Restriction of the food intake of sedentary laboratory rodents can be regarded either as life prolongation or prevention of life shortening by obesity. We compared the effects of these interventions on male Sprague-Dawley rats from the age of 5 to 23 months in the following groups: (1) RW=voluntary running in wheels; (2) PW=fed to pair weight with RW animals; (3) TM=forced training in a treadmill; and (4) S1=sedentary with ad libitum access to food. Each group consisted of 32 animals, all housed individually in cages. Two RW animals died, five died in each of the PW and S1 groups and 10 in the TM group (p<0.05). The S1 and TM groups gained most weight, the TM less after the age of 21 months (p<0.05). The body weights of the RW group was lower than those of the S1 and TM groups all the time (p<0.001) and the difference increased all the time. Body composition was analysed by bioelectrical impedance analysis. There were no differences in fat free mass (FFM) neither between RW and PW at any time, nor between S1 and TM. FFM was lower for RW and PW compared to S1 and TM. TM gained FFM until the age of 17 months, while S1 gained FFM all the time. S1 gained fat all the time, but the gain for TM levelled off. It stayed constant for RW until 13 months and decreased afterwards. We conclude that voluntary running in wheels enhances survival and keeps body fat lower than in PW animals up to the age of 17 months. Body composition and survival data suggest that voluntary running is more optimal than forced. Care must, however, be taken in analyses, since RW is a heterogenous group because there is a large variation between the animals with respect to how much they run.
Recently we have shown that an experimentally controlled encounter of mice with rats ("rat stress") some time before actual behavioural testing either abolished or induced behavioural deficits in the Morris water maze, depending on the genotype of the mice: apolipoprotein E knockout mice (apoE0/0) and wild type mice. Here we report that previous rat stress: (i) facilitated learning of a circular hole board task in apoE0/0 mice and impaired learning in wild type mice, thereby abolishing genotype-dependent differences; (ii) although both genotypes preferred the dark compartment when tested in a light/dark-preference task 3 months after rat stress, locomotor activity was reduced in apoE0/0 and increased in wild type mice, thus genotype differences were amplified; (iii) both genotypes responded with a differential regulation of bodyweight during exposure to rats, which persisted for 3 months: apoE0/0 mice decreased while wild type mice increased their body weight; (iv) the high emotional reactivity (defecation boli) measured during behavioural tasks was not affected in apoE0/0 mice, whereas a decrease was observed in wild type mice. Thus, pre-experimental confrontation of mice with rats shifts behaviour and physiological responses and eliminates some of the genotype-dependent differences.
Behavioral characterization of Alzheimer's disease (AD) transgenic models over multiple time points during aging has been largely inadequate, usually being limited to one or two cognitive-based tasks. In this context, the present study utilized a comprehensive 6-week behavioral battery to characterize sensorimotor and cognitive performance of Tg2576 AD transgenic (Tg+) mice and nontransgenic (Tg-) controls aged 3, 9, 14, and 19 months. Compared collectively to Tg- mice over all four time points, Tg+ mice were impaired in Y-maze spontaneous alternation, visible platform recognition, and several sensorimotor tasks; Tg+ mice also showed an overall increase in activity measures. The deficits in visible platform became evident by 9 months of age, while those in sensorimotor tasks became clearly manifest by 14 months. Although the behavioral impairments exhibited by Tg+ mice were usually progressive through 19 months, Tg- animals also showed similar progressive decline in the same behavioral measures; thus, no task revealed a progressive behavioral decline exclusive to Tg+ mice. Moreover, although the 6-week behavioral battery included six cognitively based tasks (i.e., Y-maze, visible platform, Morris water maze, circular platform, passive avoidance, and active avoidance), behavioral analysis through 19 months revealed Tg+ mice to be impaired in only the Y-maze and visible platform tasks. Consequently, Tg2576 mice do not exhibit widespread, profound cognitive impairment, even into old age. This may reflect their predominant C57BL/6 background and an apparent inability of the mutant transgene to profoundly alter performance therein.
A meta-analytic study was conducted to examine the hypothesis that aerobic fitness training enhances the cognitive vitality of healthy but sedentary older adults. Eighteen intervention studies published between 1966 and 2001 were entered into the analysis. Several theoretically and practically important results were obtained. Most important fitness training was found to have robust but selective benefits for cognition, with the largest fitness-induced benefits occurring for executive-control processes. The magnitude of fitness effects on cognition was also moderated by a number of programmatic and methodological factors, including the length of the fitness-training intervention, the type of the intervention, the duration of training sessions, and the gender of the study participants. The results are discussed in terms of recent neuroscientific and psychological data that indicate cognitive and neural plasticity is maintained throughout the life span.
Chronic stress is associated with hippocampal damage and impaired memory in animals and humans.
To examine this relationship with clinical and pathologic data from the Religious Orders Study.
Older Catholic clergy members underwent annual clinical evaluations, which included clinical classification of Alzheimer's disease (AD) and detailed cognitive function testing from which composite measures of global cognition and specific cognitive functions were derived. At the baseline evaluation, participants completed a measure of the tendency to experience psychological distress, a stable personality trait that served as an indicator of susceptibility to negative emotional states across the life span. More than 90% of participants who died underwent a uniform postmortem examination of the brain from which summary measures of AD pathology were derived. The association of distress proneness with incident AD and cognitive decline and with measures of AD pathology was examined in analyses adjusted for selected demographic and clinical variables.
During a mean of 4.9 years of follow-up, 140 persons developed AD. Those high in distress proneness (90th percentile) had twice the risk of developing AD than those low in distress proneness (10th percentile). Distress proneness was related to decline in episodic memory but not in other cognitive domains, with a >10-fold increase in episodic memory decline in those high in distress proneness compared with those low in the trait. Among those who died, however, distress proneness was not related to common measures of AD pathology.
Proneness to experience psychological distress is a risk factor for AD, an effect independent of AD pathologic markers such as cortical plaques and tangles.
In this study, the authors evaluated whether the association between low educational level and increased risk of Alzheimer's disease (AD) and dementia may be explained by occupation-based socioeconomic status (SES). A cohort of 931 nondemented subjects aged > or = 75 years from the Kungsholmen Project, Stockholm, Sweden, was followed for 3 years between 1987 and 1993. A total of 101 incident cases of dementia, 76 involving AD, were detected. Less-educated subjects had an adjusted relative risk of developing AD of 3.4 (95% confidence interval: 2.0, 6.0), and subjects with lower SES had an adjusted relative risk of 1.6 (95% confidence interval: 1.0, 2.5). When both education and SES were introduced into the same model, only education remained significantly associated with AD. Combinations of low education with low or high SES were associated with similar increased risks of AD, but well-educated subjects with low SES were not at high risk. Low SES at 20 years of age, even when SES was high at age 40 or 60 years, was associated with increased risk; however, this increase disappeared when education was entered into the model. In conclusion, the association between low education and increased AD risk was not mediated by adult SES or socioeconomic mobility. This suggests that early life factors may be relevant.
To investigate whether the type of physical activity, voluntary or forced, would promote different morphological changes in hippocampal formation we performed an immunocytochemical study using the parvalbumin (PV) distribution as a marker. Animals submitted to the voluntary exercise were placed in a voluntary wheel running and those submitted to the forced exercise were placed in a motor driven treadmill. Both exercise groups were submitted to 10 consecutive days of physical activity. It was observed a higher number of PV-positive cells in the hilus of dentate gyrus (DG) in the voluntary and forced exercise groups when compared to the control group. The voluntary exercise group also presented a stronger fiber staining in the DG hilus than the forced exercise and control groups. In contrast, no differences were found in the pattern of PV staining in CA1/CA3 region between exercise and control groups. These findings demonstrate that physical activity leads to prominent plastic changes in the hippocampal formation of rats that were more evident following voluntary activity.
Environmental enrichment (EE) has been shown to improve cognitive performance and brain indices of cognition in normal mice and rats. Because the therapeutic potential of intensive, long-term EE to benefit patients with Alzheimer's disease (AD) has yet to be explored, the present study evaluated the effect of long-term EE on cognition in an animal model of AD, the APPsw transgenic mouse. Beginning at 16 months of age, APPsw mice were put into EE or standard housing for 4 months and then tested in four cognitive-based tasks (Morris maze, circular platform, platform recognition, and radial arm water maze) between 20 and 22 months of age. Our results indicate that long-term EE of aged APPsw mice results in global, overall improvement in cognitive function across these tasks without decreasing brain beta-amyloid (A beta) deposition. The results suggest that long-term EE/cognitive stimulation could provide cognitive stabilization or improvement to AD patients through mechanisms independent of A beta deposition and clearance.
Tg2576 transgenic mice (mice overexpressing the "Swedish" mutation in the human amyloid precursor protein 695) demonstrated a decreased capacity for cell proliferation in the dentate gyrus of the hippocampus compared with non-transgenic littermates at 3 months, 6 months and 9 months of age. Isolation stress induced by individually housing each mouse from the time of weaning further decreased hippocampal cell proliferation in Tg2576 mice as well as in non-transgenic littermates at 6 months of age. Decreases in hippocampal cell proliferation in isolated Tg2576 mice were associated with impairments in contextual but not cued memory. Fluoxetine administration increased cell proliferation and improved contextual memory in isolated Tg2576 mice. Further, isolation stress accelerated the age-dependent deposition of beta-amyloid 42 plaques in Tg2576 mice. Numerous beta-amyloid plaques were found in isolated but not non-isolated Tg2576 mice at 6 months of age. These results suggest that Tg2576 mice, a mouse model of Alzheimer disease, have an impaired ability to generate new cells in the dentate gyrus of the hippocampus and that the magnitude of this impairment can be modulated by behavioral interventions and drugs known to have effects on hippocampal neurogenesis in normal rodents. Unexpectedly, isolation stress also appeared to accelerate the underlying process of beta-amyloid plaque deposition in Tg2576 mice. These results suggest that stress may have an impact on the underlying disease process associated with Alzheimer's disease.
We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain-derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF-mediated mechanism subserves the capacity of exercise to improve hippocampal-dependent learning. A specific immunoadhesin chimera (TrkB-IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1-week voluntary exercise period. After this, a 2-trial-per-day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response-element-binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise-induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF-mediated mechanism.
Persons without dementia residing in a biracial community completed a brief scale of proneness to psychological distress, and 1,064 were subsequently examined for incident Alzheimer disease (AD) 3 to 6 years later. In analyses controlling for selected demographic and clinical variables, persons prone to distress were 2.4 times more likely to develop AD than persons not distress prone. This effect was substantially stronger in white persons compared to African Americans.