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Alzheimer’s Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis

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Abstract

The decreased availability of metabolizable energy resources in the central nervous system is hypothesized to be a key factor in the pathogenesis of Alzheimer's disease. More specifically, the age-related decline in the ability of glucose to cross the blood-brain barrier creates a metabolic stress that shifts the normal, benign processing of amyloid-β protein precursor toward pathways associated with the production of amyloid-β plaques and tau-containing neurofibrillary tangles that are characteristic of the disease. The neuroenergetic hypothesis provides insight into the etiology of Alzheimer's disease and illuminates new approaches for diagnosis, monitoring, and treatment.
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... There are multiple proposed underlying hypotheses of Alzheimer's disease (AD) and related therapeutic strategies, in relation to normal aging [1,2]. These include metabolic/mitochondrial dysfunction leading to metabolic insufficiency [3][4][5], vascular dysfunction and stroke [6, 7], amyloid plaques [8], phosphorylated tau [3], early tau phosphorylation under low glucose conditions [9][10][11][12],and recurrent herpes viral infection [13]. Most animal models of AD, based on human mutations of either amyloid precursor protein (APP) or presenilin-1 (PS1), show progression of amyloid plaques and abnormal behavior, similar in many ways to the human aspects of worsening from normal aging to mild cognitive impairment (MCI) to frank dementia [14]. ...
... Critical advantages of animal models of AD include being able to analyze any stage of the stereotypic disease progression (based on animal age), performing aging and gender analysis, and testing results of pre-symptomatic treatment to reveal critical aspects of metabolic derangements and mechanisms. In spite of model availability for testing therapeutic approaches, few approved treatments for AD are available (anticholinergic drugs, memantine), hence fresh approaches are critical [2,4,[17][18][19]. Our hypothesis is that reduced brain glucose availability significantly contributes to neurodegeneration from a critical mismatch of dynamic metabolic supply and demand at an early point of degeneration, particularly in relation to age-matched controls. ...
... These conditions may starve neurons, exaggerate neuronal damage, and worsen dementia [54]. As predicted from human glucose uptake studies showing that impaired metabolism may occur early in dementia [4,26,61], then the metabolic insufficiency may be present over years causing progressive degeneration and the severe atrophy and neuronal loss associated with dementia. If inadequate neurovascular coupling early in the disease could be estimated by surrogate biomarkers, such as metabolic brain studies with dynamic activation [62] then these patients may be more amenable to early metabolic treatment paradigms [61]. ...
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Metabolic insufficiency and neuronal dysfunction occur in normal aging but is exaggerated in dementia and Alzheimer's disease (AD). Metabolic insufficiency includes factors important for both substrate supply and utilization in the brain. Metabolic insufficiency occurs through a number of serial mechanisms, particularly changes in cerebrovascular supply through blood vessel abnormalities (ie, small and large vessel vasculopathy, stroke), alterations in neurovascular coupling providing dynamic blood flow supply in relation to neuronal demand, abnormalities in blood brain barrier including decreased glucose and amino acid transport, altered glymphatic flow in terms of substrate supply across the extracellular space to cells and drainage into CSF of metabolites, impaired transport into cells, and abnormal intracellular metabolism with more reliance on glycolysis and less on mitochondrial function. Recent studies have confirmed abnormal neurovascular coupling in a mouse model of AD in response to metabolic challenges, but the supply chain from the vascular system into neurons is disrupted much earlier in dementia than in equivalently aged individuals, contributing to the progressive neuronal degeneration and cognitive dysfunction associated with dementia. We discuss several metabolic treatment approaches, but these depend on characterizing patients as to who would benefit the most. Surrogate biomarkers of metabolism are being developed to include dynamic estimates of neuronal demand, sufficiency of neurovascular coupling, and glymphatic flow to supplement traditional static measurements. These surrogate biomarkers could be used to gauge efficacy of metabolic treatments in slowing down or modifying dementia time course.
... The inefficient or damaged blood-brain barrier causes undesirable substances, and pathogens can invade the brain tissue provoking local inflammation that intensifies degenerative and necrotic processes. Pathological effects of unsealed the blood-brain barrier and vascular microdamage are usually augmented by increased blood pressure and type 2 diabetes [129,130]. The latter pathology is the direct effect of neuronal deficit of ATP production, resulting in decreasing absorption of glucose and the general collapse of the brain's energy metabolism. ...
... The aging of the CNS is a complex process that seems to be predominantly triggered by the dysfunction of energy metabolism [1,19,21,29,31,32,67,68,92,100,101,[130][131][132]. The effects of aging are particularly prominent in the nervous structures and functions that are most sensitive to energy deficits. ...
... Depending on morphological differences between neuronal cells and networks, there are several primary targets of the brain's aging and related deficient energy metabolism [70,89,90,93,100,133,136]. Although the etiology of neurodegenerative diseases seems still enigmatic, there is consensus for the impact of the decreased energy metabolism, excitotoxicity, and oxidative damage on their development [18,19,31,65,130]. Mitochondria, as energetic cellular centers, are particularly susceptible to energy deficit and oxidative stress. ...
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There is a growing body of evidencethat indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production—which, in turn, limits glucose access. This vicious circle of energy metabolism at the cellular level is evoked by a rising deficiency of nicotinamide adenine dinucleotide (NAD) in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle. A decreasing NAD level also impoverishes the activity of NAD-dependent enzymes that augments genetic errors and initiate processes of neuronal degeneration and death.This sequence of events is characteristic of several brain structures in which neurons have the highest energy metabolism. Neurons of the cerebral cortex and basal ganglia with long unmyelinated axons and these with numerous synaptic junctions are particularly prone to senescence and neurodegeneration. Unfortunately, functional deficits of neurodegeneration are initially well-compensated, therefore, clinical symptoms are recognized too late when the damages to the brain structures are already irreversible. Therefore, future treatment strategies in neurodegenerative disorders should focus on energy metabolism and compensation age-related NAD deficit in neurons. This review summarizes the complex interrelationships between metabolic processes on the systemic and cellular levels and provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.
... These two metabolites are classified as acylcarnitine and changes in the level of acylcarnitines can be an indicator of metabolic disorders (Koeberl et al., 2003;Millington & Stevens, 2011). It has been documented that metabolic dysfunction is a prominent feature in the AD brain (Blonz, 2017) and disorders such as diabetes can be associated with AD (Craft, 2009). ...
... This pathway is involved in the energy production process in the brain as it can produce metabolic intermediates that can be directly utilised by glycolysis and the Krebs cycle (Kanehisa & Goto, 2000). AD has been linked to energy production deficiency (Blonz, 2017) and the results from our metabolomics analysis support the role of energy production deficits in the presymptomatic stage of AD. Furthermore, pyrimidine metabolism pathway was also identified as significantly enriched and recently, the literature has associated pyrimidine metabolism with AD (Muguruma et al., 2020). ...
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IntroductionThe mechanistic role of amyloid precursor protein (APP) in Alzheimer’s disease (AD) remains unclear.Objectives Here, we aimed to identify alterations in cerebral metabolites and metabolic pathways in cortex, hippocampus and serum samples from Tg2576 mice, a widely used mouse model of AD.Methods Metabolomic profilings using liquid chromatography-mass spectrometry were performed and analysed with MetaboAnalyst and weighted correlation network analysis (WGCNA).ResultsExpressions of 11 metabolites in cortex, including hydroxyphenyllactate—linked to oxidative stress—and phosphatidylserine—lipid metabolism—were significantly different between Tg2576 and WT mice (false discovery rate < 0.05). Four metabolic pathways from cortex, including glycerophospholipid metabolism and pyrimidine metabolism, and one pathway (sulphur metabolism) from hippocampus, were significantly enriched in Tg2576 mice. Network analysis identified five pathways, including alanine, aspartate and glutamate metabolism, and mitochondria electron transport chain, that were significantly correlated with AD genotype.Conclusions Changes in metabolite concentrations and metabolic pathways are present in the early stage of APP pathology, and may be important for AD development and progression.
... Additionally, relevant to DS neuropathology, some other genes on Hsa21 include SOD-1 (superoxide . Fig. 28 [84,85], supported by the failure of multiple clinical trials targeting amyloid [86]. Yet, the ACH accommodates a wide range of data that we have on the aetiopathogenesis of DS-AD into a coherent hypothesis. ...
... Neurodegenerative diseases are characterized by progressive damage to the nervous tissue. Alzheimer's disease (AD) is considered one of the most frequent diseases and here we contemplate multiple factors that trigger its onset [1,2], such as genetic disposition due to variations present in the genes that translate proteins such as presenilin-1 (PS1), presenilin-2 (PS2), and amyloid precursor protein (APP) [3][4][5]. Similarly, the disease can be acquired due to sporadic disposition due to risk factors such as low physical and cognitive activity, toxicity due to bioaccumulation of metals in the brain such as copper and zinc, or due to a high-fat diet [6,7]. ...
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Alzheimer’s disease manifests itself in brain tissue by neuronal death, due to aggregation of β-amyloid, produced by senile plaques, and hyperphosphorylation of the tau protein, which produces neurofibrillary tangles. One of the genetic markers of the disease is the gene that translates the presenilin-2 protein, which has mutations that favor the appearance of the disease and has no reported crystallographic structure. In view of this, protein modeling is performed using prediction and structural refinement tools followed by an energetic and stereochemical characterization for its validation. For the simulation, four reported mutations are chosen, which are Met239Ile, Met239Val, Ser130Leu, and Thr122Arg, all associated with various functional responses. From a theoretical analysis, a preliminary bioinformatic study is made to find the phosphorylation patterns in the protein and the hydropathic index according to the polarity and chemical environment. Molecular visualization was carried out with the Chimera 1.14 software, and the theoretical calculation with the hybrid quantum mechanics/molecular mechanics system from the semi-empirical method, with Spartan18 software and an AustinModel1 basis. These relationships allow for studying the system from a structural approach with the determination of small distance changes, potential surfaces, electrostatic maps, and angle changes, which favor the comparison between wild-type and mutant systems. With the results obtained, it is expected to complement experimental data reported in the literature from models that would allow us to understand the effects of the selected mutations.
... Brain insulin resistance (IR) can develop in the absence of systemic IR (82) , but epidemiological and neuroimaging studies consistently report a strong association between type 2 diabetes and AD, suggesting that both peripheral and central IR usually co-exist (83,84) . In patients with AD, impaired insulin action may contribute to abnormal brain energetics in several ways including impaired mitochondrial oxidative metabolism and ATP-dependent maintenance processes that are critical to neuronal survival (85) . Moreover, increased production of reactive species and inflammatory cytokines resulting from reduced brain insulin signalling damage brain cell structure and functional integrity (86) . ...
Article
Alzheimer’s disease (AD) is the most common major neurocognitive disorder of aging. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) - to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during aging. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimizing the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.
... These conditions may starve neurons and cause heightened neuronal damage and worsening dementia. 8 As predicted from human glucose uptake studies showing that impaired metabolism may occur early in dementia, 2,9,10 metabolic insufficiency in the brain may be present over years, causing progressive degeneration and the severe atrophy and neuronal loss associated with dementia. If inadequate neurovascular coupling early in the disease could be estimated by surrogate biomarkers, such as metabolic brain studies with dynamic activation 11 then these patients may be more amenable to early metabolic treatment paradigms. ...
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We compared the efficacy of neurovascular coupling and substrate supply in cerebral cortex during severe metabolic challenges in transgenic Alzheimer's [CVN-AD] and control [C57Bl/6] mice, to evaluate the hypothesis that metabolic insufficiency is a critical component of degeneration leading to dementia. We analyzed cerebral blood flow and metabolic responses to spreading depression (induced by K+ applied to the cortex) and anoxia across aging in CVN-AD + C57Bl/6 genotypes. In the CVN-AD genotype progression to histological and cognitive hallmarks of dementia is a stereotyped function of age. We correlated physiology and imaging of the cortex with the blood flow responses measured with laser doppler probes. The results show that spreading depression resulted in a hyperemic blood flow response that was dramatically reduced (24% in amplitude, 70% in area) in both middle-aged and aged CVN-AD mice compared to C57Bl/6 age-matched controls. However, spreading depression amplitude and conduction velocity (≈6 mm/min) did not differ among groups. Anoxia (100% N2 ) showed significantly decreased (by 62%) reactive blood flow and autoregulation in aged AD-CVN mice compared to aged control animals. Significantly reduced neurovascular coupling occurred prematurely with aging in CVN-AD mice. Abbreviated physiological hyperemia and decreased resilience to anoxia may enhance early-onset metabolic deficiency through decreased substrate supply to the brain. Metabolic deficiency may contribute significantly to the degeneration associated with dementia as a function of aging and regions of the brain involved.
Chapter
Astrocytes respond to any pathological stimulus to the central nervous system including in Alzheimer’s disease (AD). They undergo dramatic remodeling at the molecular, cellular, and functional levels to constitute a heterogeneous population across disease stages that are collectively termed as reactive astrocytes. “Astrocyte reactivity” or “reactive astrogliosis” encompasses multiple distinct states astrocytes adopt across the disease stages. For several decades this phenomenon has been considered a nonspecific reaction to pathological insults without any disease-inducing mechanisms and with no therapeutic value. Recent studies have contrarily underscored the specific roles of astrocytes in disease pathogenesis. With the advent of single-cell and single-nucleus transcriptomics, numerous disease-modifying functions of reactive astrocytes are revealed. Diverse subtypes of reactive astrocytes are currently the major focus of AD research. Previously astrocytes were thought to contribute towards neuronal degeneration by releasing pro-inflammatory mediators in AD. Present evidences indicate that reactive astrocytes also play a pivotal role in neuroprotection, plausibly at the prodromal AD stages by secreting anti-inflammatory molecules, clearing Aβ and limiting neuroinflammation in the CNS. In this chapter we attempt to review the extensive yet subtle functional diversities in reactive astrocytes in AD with respect to metabolic alterations, neuroinflammation, Aβ production and clearance, tau pathology, synaptic plasticity, neurotransmitter recycling, and their impact on neuronal health. We further highlight their contribution in identifying early-stage AD biomarkers. Thus, reactive astrocytes may represent an attractive therapeutic target in halting AD progression, its prevention, or in cure.
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Purpose: Studies on quantitative susceptibility mapping (QSM) have reported an increase in magnetic susceptibilities in patients with Alzheimer's disease (AD). Despite the pathological importance of the brain surface areas, they are sometimes excluded in QSM analysis. This study aimed to reveal the efficacy of QSM analysis with brain surface correction (BSC) and/or vein removal (VR) procedures. Methods: Thirty-seven AD patients and 37 age- and sex-matched, cognitively normal (CN) subjects were included. A 3D-gradient echo sequence at 3T MRI was used to obtain QSM. QSM images were created with regularization enabled sophisticated harmonic artifact reduction for phase data (RESHARP) and constrained RESHARP with BSC and/or VR. We conducted ROI analysis between AD patients and CN subjects who did or did not undergo BSC and/or VR using a t-test, to compare the susceptibility values after gray matter weighting. Results: The susceptibility values in RESHARP without BSC were significantly larger in AD patients than in CN subjects in one region (precentral gyrus, 8.1 ± 2.9 vs. 6.5 ± 2.1 ppb) without VR and one region with VR (precentral gyrus, 7.5 ± 2.8 vs. 5.9 ± 2.0 ppb). Three regions in RESHARP with BSC had significantly larger susceptibilities without VR (precentral gyrus, 7.1 ± 2.0 vs. 5.9 ± 2.0 ppb; superior medial frontal gyrus, 5.7 ± 2.6 vs. 4.2 ± 3.1 ppb; putamen, 47,8 ± 16.5 vs. 40.0 ± 15.9 ppb). In contrast, six regions showed significantly larger susceptibilities with VR in AD patients than in CN subjects (precentral gyrus, 6.4 ± 1.9 vs. 4.9 ± 2.7 ppb; superior medial frontal gyrus, 5.3 ± 2.7 vs. 3.7 ± 3.3 ppb; orbitofrontal cortex, -2.1 ± 2.7 vs. -3.6 ± 3.2 ppb; parahippocampal gyrus, 0.1 ± 3.6 vs. -1.7 ± 3.7 ppb; putamen, 45.0 ± 14.9 vs. 37.6 ± 14.6 ppb; inferior temporal gyrus, -3.4 ± 1.5 vs. -4.4 ± 1.5 ppb). Conclusion: RESHARP with BSC and VR showed more regions of increased susceptibility in AD patients than in CN subjects. This study highlights the efficacy of this method in facilitating the diagnosis of AD.
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This article updates the Calcium Hypothesis of Alzheimer's disease and brain aging on the basis of emerging evidence since 1994 (The present article, with the subtitle "New evidence for a central role of Ca2+ in neurodegeneration," includes three appendices that provide context and further explanations for the rationale for the revisions in the updated hypothesis-the three appendices are as follows: Appendix I "Emerging concepts on potential pathogenic roles of [Ca2+]," Appendix II "Future studies to validate the central role of dysregulated [Ca2+] in neurodegeneration," and Appendix III "Epilogue: towards a comprehensive hypothesis.") (Marx J. Fresh evidence points to an old suspect: calcium. Science 2007; 318:384-385). The aim is not only to re-evaluate the original key claims of the hypothesis with a critical eye but also to identify gaps in knowledge required to validate relevant claims and delineate additional studies and/or data that are needed. Some of the key challenges for this effort included examination of questions regarding (1) the temporal and spatial relationships of molecular mechanisms that regulate neuronal calcium ion (Ca2+), (2) the role of changes in concentration of calcium ion [Ca2+] in various subcellular compartments of neurons, (3) how alterations in Ca2+ signaling affect the performance of neurons under various conditions, ranging from optimal functioning in a healthy state to conditions of decline and deterioration in performance during aging and in disease, and (4) new ideas about the contributions of aging, genetic, and environmental factors to the causal relationships between dysregulation of [Ca2+] and the functioning of neurons (see Appendices I and II). The updated Calcium Hypothesis also includes revised postulates that are intended to promote further crucial experiments to confirm or reject the various predictions of the hypothesis (see Appendix III).
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As populations across the world both age and become more obese, the numbers of individuals with Alzheimer′s disease and diabetes are increasing; posing enormous challenges for society and consequently becoming priorities for governments and global organizations. These issues, an ageing population at risk of neurodegenerative diseases such as Alzheimer′s disease and an increasingly obese population at risk of metabolic alterations such as type 2 diabetes, are usually considered as independent conditions, but increasing evidence from both epidemiological and molecular studies link these disorders. The aim of this review was to highlight these multifactorial links. We will discuss the impact of direct links between insulin and IGF-1 signalling and the Alzheimer′s disease-associated pathological events as well as the impact of other processes such as inflammation, oxidative stress and mitochondrial dysfunction either common to both conditions or perhaps responsible for a mechanistic link between metabolic and neurodegenerative disease. An understanding of such associations might be of importance not only in the understanding of disease mechanisms but also in the search for novel therapeutic options.
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Background: Alzheimer's disease (AD) is characterized by neuronal degeneration, vascular pathology and cognitive decline. Furthermore, deficits in cerebral glucose metabolism and insulin resistance are being increasingly recognized in AD. Many lifestyle-modifying approaches, including diet and exercise, have yielded promising results in modulating brain morphology and function for the prevention and early treatment of AD. Objective: This review focuses on the effects of physical exercise on rescuing cognition and limiting the progression of AD pathology. Specifically, the impact of exercise, in human and animal models of AD, on the stimulation and preservation of cognition, neurotransmission, neurogenesis, vasculature, glucose metabolism and insulin signaling is discussed. Conclusion: Studies have highlighted the potential of physical activity to improve overall brain health, which could delay or lessen AD-related cognitive deficits and pathology. Physical activity influences cognitive function, vascular health and brain metabolism, which taken together offers benefits for the aging population, including AD patients.