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Exercise hormone irisin is a critical regulator of cognitive function

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Abstract and Figures

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.
Irisin deletion impairs cognitive function in exercise and aging a, Schematic of flox targeting-construct for the Fndc5 locus. b, Bodyweights (WT-sed n = 9; WT-run n = 12; F5KO-sed n = 12; F5KO-run, n = 14). c, qPCR of Fndc5 mRNA expression (n.d.: no detection) (n = 3 per group). d and e, Plasma irisin with commercial ELISA (n = 4 per group) (d) or EIA (n = 2 per group) (e). f, Rotarod, g, Grip strength, h, Gait scan analysis: average propulsion (left) and swing time (right). FR = front right limb, FL = front left, RR = rear right, RL = rear left (WT n = 6, F5KO n = 10), i, Open field test (OPF) (WT-sed n = 5; WT-run n = 6; F5KO-sed n = 6; F5KO-run n = 6), and j, Running activity and k and l, Morris-water-maze (MWM): latency to reach target platform (k) and 24 h probe trial in acquisition (l). NE (red bar) was the target quadrant (WT-sed n = 9; WT-run, n = 12; F5KO-sed n = 12; F5KO-run, n = 14). m, Swim speed, 9-months-old mice (WT, n = 10, F5KO, n = 10). n and o, Novel object recognition (NOR) task in young (n) (WT n = 12, F5KO, n = 14) and aged mice (o) (WT n = 5, F5KO, n = 7). p and q, Bodyweights (p) and Open field test (OPF) (q) for aged mice (WT n = 8, F5KO, n = 7). r, Spontaneous alternation behavior (SAB) in aged mice (WT, n = 7, F5KO, n = 7). s and t, Electrophysiology in DG using acute slices, paired pulse ratio (s) and EPSP input-output curve (t) (WT n = 14, F5KO n = 15 slices, 7 animals per group,). RM-Two-way ANOVA (k, t), Two-way ANOVA (b, h, i), One-way ANOVA. Significance was assigned only if time spent in the target quadrant was significantly different from all other quadrants (l), Two-tailed t-test (d-g, j, m-s). ***p < 0.001, ****p < 0.0001 n.s.= not significant. Data represented as mean ± SEM of biologically independent samples. See source data for exact p-values. Source data
Adult-born neurons in the hippocampus are altered in global F5KO mice a and b, Quantification (a) and representative immunohistochemistry images (b) of BrdU+ adult-born hippocampal neurons in WT and F5KO mice (n = 6 per group). Scale bar 100 μm. c and d, Quantification (c) and representative immunofluorescence images (d) of EdU+ adult-born hippocampal neurons in WT and F5KO mice with or without running exercise (WT-sed n = 8, WT-run n = 10, F5KO n = 8, F5KO-run n = 13). Scale bar 100 μm. e, Soma size of adult-born hippocampal neurons (WT-sed n = 60, WT-run n = 60, F5KO-sed n = 65, F5KO-run n = 64 neurons). f-h, Dendritic spine analysis of newborn neurons in the ventral hippocampus. Dendritic spines density (f), cumulative distribution of spine head width (g), and median spine head width (h) (WT-sed n = 7, WT-run n = 6, F5KO-sed n = 7, F5KO-run n = 6 (f); WT-sed n = 1239, WT-run n = 1056, F5KO-sed n = 1089, F5KO-run n = 1047 spines (g); WT-sed n = 7, WT-run n = 6, F5KO-sed n = 6, F5KO-run n = 6 (h)). i-l, Dendritic spine analysis in mature granule cells in the dentate gyrus of Thy1-GFP/WT and Thy1-GFP/F5KO. Representative confocal images of dendritic spines stained with anti-GFP (green). Scale bar 5 µm (i), dendritic spines density (j), cumulative distribution of spine head width (k), and median spine head width (l) (n = 5 per group (j, l); WT n = 921, F5KO n = 948 spines (k)). Two-way ANOVA (c, e, f, h), Kruskal-Wallis ANOVA (g), Kolmogorov-Smirnov test (k), Two-tailed t-test (a, j, l). *p < 0.05, ****p < 0.0001, n.s.= not significant. Data are represented as mean ± SEM of biologically independent samples, except for violin plots with center line = median, dotted line = upper and lower quartile (e). See source data for exact p-values. Source data
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1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 2Program in Behavioral Neuroscience,
Northeastern University, Boston, MA, USA. 3Harvard NeuroDiscovery Center, Brigham and Women’s Hospital and Harvard Medical School, Boston,
MA, USA. 4Division of Medical Sciences, University of Victoria, Victoria, British Colombia, Canada. 5Nephrology Division, Department of Medicine,
Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 6Center for Regenerative Medicine, Massachusetts General Hospital
and Harvard Medical School, Boston, MA, USA. 7Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard
Medical School, Boston, MA, USA. 8LakePharma, San Carlos, CA, USA. 9MassGeneral Institute for Neurodegenerative Disease, Genetics and Aging
Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. 10McCance Center
for Brain Health, Massachusetts General Hospital, Boston, MA, USA. 11These authors contributed equally: Mohammad R. Islam, Sophia Valaris.
Preserving cognitive function is a major challenge in an increas-
ingly ageing population. Despite best efforts, traditional
approaches to develop effective therapies have been largely
unsuccessful. Interestingly, exercise, especially endurance exercise,
is known to have beneficial effects on brain health and can improve
cognitive function during ageing13. Furthermore, higher physical
activity levels are associated with reduced risk of AD and lesser
cognitive decline in AD4. These positive effects are in part due to
enhanced adult hippocampal neurogenesis and synaptic plasticity
in the dentate gyrus (DG) of the hippocampus as well as reduced
neuroinflammation57. Identification of secreted factors that may
mediate these neuroprotective effects of exercise represent very
attractive drug targets.
FNDC5 (fibronectin-domain III containing 5) is a glycosylated
type 1 membrane protein and has been identified as an important
exercise-regulated factor that induces major metabolic benefits8.
Exercise also induces hippocampal Fndc5 expression in mice and
FNDC5 can activate hippocampal neuroprotective genes9. FNDC5
is proteolytically cleaved and the N-terminal portion of this is
released into the circulation; the secreted form of FNDC5 has been
named irisin (Fig. 1a). Irisin contains 112 amino acids, is heavily
glycosylated and is 100% conserved between mouse and human.
The structure of irisin and its elevation with endurance exercise in
humans has been confirmed using tandem mass spectrometry of
human plasma10. In bone and fat, irisin mediates its effects via αV
integrin receptors11.
Although previous work has implicated the FNDC5 pathway in
exercise benefits and in AD9,12, it remains unknown whether iri-
sin itself, the cleaved, circulating part of FNDC5, rather than the
full-length membrane-bound form, is the active moiety. From a
translational point of view, having the neuroprotective effects con-
ferred in a small natural hormone versus a membrane protein is
crucial. Here, we show that genetic deletion of Fndc5/irisin impairs
cognitive function in exercise, ageing and AD, in part by altera-
tions of adult newborn neurons in the hippocampus. We further
determine that irisin is the active moiety mediating the cognitive
benefits. Most importantly, we demonstrate that peripheral applica-
tion of irisin is sufficient to rescue the cognitive decline in mouse
models of AD.
Irisin deletion impairs cognitive function in exercise and ageing.
To investigate the physiological role of FNDC5/irisin in exercise, we
generated Fndc5fl/fl-targeted mice and crossed them with germline
EIIa-cre mice to generate global F5KO mice. The floxed targeting
construct was designed to delete exon 3 and 4, and thereby irisin
portions of the Fndc5 gene (Extended Data Fig. 1a). The mice were
born in an approximate Mendelian ratio with no gross abnormalities
Exercise hormone irisin is a critical regulator of
cognitive function
Mohammad R. Islam1,11, Sophia Valaris1,11, Michael F. Young1, Erin B. Haley1, Renhao Luo1,
Sabrina F. Bond1,2, Sofia Mazuera1,2, Robert R. Kitchen 1, Barbara J. Caldarone3, Luis E. B. Bettio4,
Brian R. Christie 4, Angela B. Schmider5, Roy J. Soberman5, Antoine Besnard 6,
Mark P. Jedrychowski7, Hyeonwoo Kim7, Hua Tu8, Eunhee Kim9,10, Se Hoon Choi9,10, Rudolph E. Tanzi 9,10,
Bruce M. Spiegelman 7 and Christiane D. Wrann 1,10 ✉
Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive
decline in ageing or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced
membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin
(global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separa-
tion in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moi-
ety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal.
Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in
the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD
mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating
cognitive disorders including AD.
NATURE METABOLISM | VOL 3 | AUGUST 2021 | 1058–1070 |
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... Wrann et al. (2013) reported that irisin stimulates the expression of brain-derived neurotrophic factor (BDNF) in cultured neurons (Wrann et al., 2013), and we have demonstrated that irisin engenders cAMP/PKA/pCREB signaling in brain explants (Lourenco et al., 2019). Recently, αVβ5 integrin has been suggested as a potential receptor for irisin in the brain (Islam et al., 2021). However, the signaling mechanisms initiated by irisin in the brain are not completely understood. ...
... Recent studies suggest that irisin controls memory function (Lourenco et al., 2019Jodeiri Farshbaf et al., 2020;Islam et al., 2021). The current study demonstrates that irisin signaling engages transient ERK phosphorylation (activation), increases extracellular BDNF, and prevents AβO-induced oxidative stress. ...
... Here we further demonstrate that cAMP accumulation by the adenylyl cyclase activator, forskolin, promotes ERK phosphorylation, raising the possibility that ERK activation is downstream of cAMP. Although aVβ5 integrin has been identified as a putative irisin receptor in the brain (Islam et al., 2021), the receptor(s) required for these effects induced by irisin in hippocampal neurons and the potential contribution of glial cells remain elusive. It is conceivable that irisin may exert pleiotropic actions in the brain by activating multiple signaling pathways in distinct brain cells (e.g., neurons and glial cells). ...
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Physical exercise stimulates neuroprotective pathways, has pro-cognitive actions, and alleviates memory impairment in Alzheimer’s disease (AD). Irisin is an exercise-linked hormone produced by cleavage of fibronectin type III domain containing protein 5 (FNDC5) in skeletal muscle, brain and other tissues. Irisin was recently shown to mediate the brain benefits of exercise in AD mouse models. Here, we sought to obtain insight into the neuroprotective actions of irisin. We demonstrate that adenoviral-mediated expression of irisin promotes extracellular brain derived neurotrophic factor (BDNF) accumulation in hippocampal cultures. We further show that irisin stimulates transient activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and prevents amyloid-β oligomer-induced oxidative stress in primary hippocampal neurons. Finally, analysis of RNA sequencing (RNAseq) datasets shows a trend of reduction of hippocampal FNDC5 mRNA with aging and tau pathology in humans. Results indicate that irisin activates protective pathways in hippocampal neurons and further support the notion that stimulation of irisin signaling in the brain may be beneficial in AD.
... Irisin levels increase in the blood of humans with exercise training, as determined by tandem mass spectrometry (8). In adipose cells, osteocytes, osteoclasts, and astrocytes integrin αV/β5 is the major functioning receptor for irisin (9,10). ...
... These findings would seem to have translational promise as a disease-modifying therapy for treating PD and other neurodegenerative diseases involving pathologic α-syn. levels of the mature, cleaved irisin using adeno-associated virus (AAV) was sufficient to improve cognitive function and reduce neuroinflammation in two distinct models of AD (9). Furthermore, irisin itself crossed the blood-brain barrier (BBB), at least when the protein was produced from the liver with these AAV vectors. ...
... To determine whether irisin can prevent pathologic α-syn-induced degeneration in vivo, α-syn PFF were stereotaxically injected into the striatum of mice (17,18). The protective role of irisin was evaluated by use of an AAV-irisin vector (AAV8) that is mainly taken up by the liver after tail vein injection and elevates circulating irisin (9). Two weeks after the intrastriatal α-syn PFF injection, mice were either injected via the tail vein with AAV8-irisin-FLAG or as a control, AAV8-GFP ( Fig. 2A). ...
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Physical activity provides clinical benefit in Parkinson’s disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood–brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.
... Similarly, exercise protected against the reduction of hippocampal Fndc5 expression induced by AbOs, but the positive effects were blocked by peripheral administration of anti-FNDC5 (13). Additionally, elevating serum irisin levels via overexpression of irisin in liver via adenoviral vectors led to increment in cerebral expression of irisin sufficient to protect against cognitive impairment and neural pathology in AD mice (117). Those data suggest that circulating irisin could cross the BBB and modulate the neural protective effects of exercise on neural plasticity and memory in AD. ...
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The physiological functions of organs are intercommunicated occurring through secreted molecules. That exercise can improve the physiological function of organs or tissues is believed by secreting myokines from muscle to target remote organs. However, the underlying mechanism how exercise regulates the inter-organ communications remains incompletely understood yet. A recently identified myokine–irisin, primarily found in muscle and adipose and subsequently extending to bone, heart, liver and brain, provides a new molecular evidence for the inter-organ communications. It is secreted under the regulation of exercise and mediates the intercommunications between exercise and organs. To best our understanding of the regulatory mechanism, this review discusses the recent evidence involving the potential molecular pathways of the inter-organ communications, and the interactions between signalings and irisin in regulating the impact of exercise on organ functions are also discussed.
... Moreover, fndc5 knockout Knock out (KO) mice had abnormal morphology and function of dentate gyrus neurons (part of the hippocampus), and the cognitive function of the mutant mice was significantly inhibited. Direct or peripheral delivery of irisin to the dentate gyrus was sufficient to ameliorate the cognitive deficits and neuropathology of the mice (44). In the mouse cerebral ischemia model induced by middle cerebral artery occlusion, the level of irisin was negatively correlated with the cerebral infarction volume and brain function injury score, whereas in those treated with r-irisin, the cerebral infarction volume, nerve function injury, and brain edema of the mice were significantly improved, which were related with phosphorylation of ERK1/2-Akt-mediated inflammation (39). ...
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Irisin, out-membrane part of fibronectin type III domain–containing 5 protein (FNDC5), was activated by Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) during physical exercise in skeletal muscle tissues. Most studies have reported that the concentration of irisin is highly associated with health status. For instance, the level of irisin is significantly lower in patients with obesity, osteoporosis/fractures, muscle atrophy, Alzheimer’s disease, and cardiovascular diseases (CVDs) but higher in patients with cancer. Irisin can bind to its receptor integrin αV/β5 to induce browning of white fat, maintain glucose stability, keep bone homeostasis, and alleviate cardiac injury. However, it is unclear whether it works by directly binding to its receptors to regulate muscle regeneration, promote neurogenesis, keep liver glucose homeostasis, and inhibit cancer development. Supplementation of recombinant irisin or exercise-activated irisin might be a successful strategy to fight obesity, osteoporosis, muscle atrophy, liver injury, and CVDs in one go. Here, we summarize the publications of FNDC5/irisin from PubMed/Medline, Scopus, and Web of Science until March 2022, and we review the role of FNDC5/irisin in physiology and pathology.
... Exercise-induced irisin can cross the blood-brain barrier with the help of peripheral transport before entering the central nervous system and inducing BDNF expression (46). The receptor of irisin in the neonatal brain is reported to be an integrin αV/β5 heterodimer while that in the adult brain remains untouched (47). ...
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Despite being one of the greatest global challenges for health and social care in the 21st century, Alzheimer’s disease (AD) lacks specific medicine. Irisin, an exercise-generated muscle factor, emerges as a potential hormone for AD prevention and treatment because of its role in promoting the browning of white adipose tissue, accelerating energy expenditure, regulating energy metabolism, and improving insulin resistance. The study reviews classic hallmarks of AD and irisin’s physiology before discussing the possible mechanism by which irisin protects against AD in terms of its effects related to molecular biology and cellular biology. Results reveal that irisin sharpens learning memory by inducing the production of brain-derived neurotrophic factor (BDNF), lowers the production of inflammatory factors, protects neurology through astrocytes, and ameliorates AD symptoms by improving insulin resistance. The review aims to facilitate future experimental studies and clinical applications of irisin in preventing and treating AD.
... AD is a complex disease, with the disease likely influenced by a complicated interplay of genetic and environmental factors such as smoking [15], diet [16], and exercise [17]. DNA methylation (DNAm) is an epigenetic mechanism that regulates gene expression without altering DNA sequence, and it is susceptible to environmental factors that modify the risk of diseases [18]. ...
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Background Sex is increasingly recognized as a significant factor contributing to the biological and clinical heterogeneity in AD. There is also growing evidence for the prominent role of DNA methylation (DNAm) in Alzheimer’s disease (AD). Methods We studied sex-specific DNA methylation differences in the blood samples of AD subjects compared to cognitively normal subjects, by performing sex-specific meta-analyses of two large blood-based epigenome-wide association studies (ADNI and AIBL), which included DNA methylation data for a total of 1284 whole blood samples (632 females and 652 males). Within each dataset, we used two complementary analytical strategies, a sex-stratified analysis that examined methylation to AD associations in male and female samples separately, and a methylation-by-sex interaction analysis that compared the magnitude of these associations between different sexes. After adjusting for age, estimated immune cell type proportions, batch effects, and correcting for inflation, the inverse-variance fixed-effects meta-analysis model was used to identify the most consistent DNAm differences across datasets. In addition, we also evaluated the performance of the sex-specific methylation-based risk prediction models for AD diagnosis using an independent external dataset. Results In the sex-stratified analysis, we identified 2 CpGs, mapped to the PRRC2A and RPS8 genes, significantly associated with AD in females at a 5% false discovery rate, and an additional 25 significant CpGs (21 in females, 4 in males) at P-value < 1×10⁻⁵. In methylation-by-sex interaction analysis, we identified 5 significant CpGs at P-value < 10⁻⁵. Out-of-sample validations using the AddNeuroMed dataset showed in females, the best logistic prediction model included age, estimated immune cell-type proportions, and methylation risk scores (MRS) computed from 9 of the 23 CpGs identified in AD vs. CN analysis that are also available in AddNeuroMed dataset (AUC = 0.74, 95% CI: 0.65–0.83). In males, the best logistic prediction model included only age and MRS computed from 2 of the 5 CpGs identified in methylation-by-sex interaction analysis that are also available in the AddNeuroMed dataset (AUC = 0.70, 95% CI: 0.56–0.82). Conclusions Overall, our results show that the DNA methylation differences in AD are largely distinct between males and females. Our best-performing sex-specific methylation-based prediction model in females performed better than that for males and additionally included estimated cell-type proportions. The significant discriminatory classification of AD samples with our methylation-based prediction models demonstrates that sex-specific DNA methylation could be a predictive biomarker for AD. As sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding of the epigenetic architecture that underlie AD and for promoting precision medicine in AD.
... In the present study, a panel of 16 biochemical parameters in serum samples from elderly patients undergoing elective orthopedic surgery were assessed, including brain derived neurotrophic factor (BDNF), fibroblast growth factor-23 (FGF-23), irisin, C3a, C3, C5a, interleukin-17A (IL-17A), interleukin-33 (IL-33), prostaglandin E2 (PGE2), S100β, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), vascular cell adhesion molecule 1 (VCAM1), E-selectin and matrix metalloprotein 9 (MMP9). Among them, BDNF, FGF-23 and irisin were selected because they are associated with neurocognitive regulation [14][15][16]. S100β, NfL and GFAP were implicated in neuronal injury [17,18]. In addition, biochemical parameters associated with complement cascade (C3a, C3, C5a) and inflammatory response (IL-17A, IL-33, E-selectin, MMP9) were involved as well. ...
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Background Postoperative delirium (POD), one of the most common complications following major surgery, imposes a heavy burden on patients and society. The objective of this exploratory study was to conduct a secondary analysis to identify whether there exist novel and reliable serum biomarkers for the prediction of POD. Methods A total of 131 adult patients (≥ 65 years) undergoing lower extremity orthopedic surgery with were enrolled in this study. Cognitive function was assessed preoperatively with Mini-Mental State Examination (MMSE). Delirium was diagnosed according to the Confusion Assessment Method (CAM) criteria on preoperative day and postoperative days 1–3. The preoperative serum levels of a panel of 16 biochemical parameters were measured by ELISA. Results Thirty-five patients developed POD, with an incidence of 26.7%. Patients in POD group were older ( P = 0.001) and had lower preoperative MMSE scores ( P = 0.001). Preoperative serum levels of prostaglandin E2 (PGE2, P < 0.001), S100β ( P < 0.001), glial fibrillary acidic protein ( P < 0.001) and neurofilament light ( P = 0.002) in POD group were significantly increased. Logistic regression analysis showed that advanced age (OR = 1.144, 95%CI: 1.008 ~ 1.298, P = 0.037), higher serum neurofilament light (OR = 1.003, 95%CI: 1.000 ~ 1.005, P = 0.036) and PGE2 (OR = 1.031, 95%CI: 1.018 ~ 1.044, P < 0.001) levels were associated with the development of POD. In addition, serum level of PGE2 yielded an area under the ROC curve (AUC) of 0.897 to predict POD ( P < 0.001), with a sensitivity of 80% and a specificity of 83.3%. Conclusions Our study showed that higher preoperative serum PGE2 level might be a biomarker to predict the occurrence of POD in elderly patients undergoing elective orthopedic surgery. Trial registration NCT03792373 .
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The term “neural plasticity” was first used to describe non-pathological changes in neuronal structure. Today, it is generally accepted that the brain is a dynamic system whose morphology and function is influenced by a variety of factors including stress, diet, and exercise. Neural plasticity involves learning and memory, the synthesis of new neurons, the repair of damaged connections, and several other compensatory mechanisms. It is altered in neurodegenerative disorders and following damage to the central or peripheral nervous system. Understanding the mechanisms that regulate neural plasticity in both healthy and diseased states is of significant importance to promote cognition and develop rehabilitation techniques for functional recovery after injury. In this minireview, we will discuss the mechanisms by which environmental factors promote neural plasticity with a focus on exercise- and diet-induced factors. We will highlight the known circulatory factors that are released in response to exercise and discuss how all factors activate pathways that converge in part on the activation of BDNF signaling. We propose to harness the therapeutic potential of exercise by using BDNF as a biomarker to identify novel endogenous factors that promote neural plasticity. We also discuss the importance of combining exercise factors with dietary factors to develop a lifestyle pill for patients afflicted by CNS disorders.
Aims Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease whose molecular mechanisms remain unclear. This study aimed to explore the role and mechanisms of microRNA-376b-3p in NAFLD. Materials and methods We used a microarray to reveal hepatic microRNA expression profiles and validated their expression in cellular and mouse models via qRT–PCR. In vitro, the expression of microRNA-376b-3p was increased by a microRNA-376b-3p mimic and decreased by a microRNA-376b-3p inhibitor. The role and potential mechanisms of microRNA-376b-3p in NAFLD were investigated in mice injected with lentiviral vectors before high-fat diet (HFD) feeding, and the direct target gene was explored using a dual-luciferase reporter gene assay and confirmed by Western blotting. Key findings Microarray analysis and subsequent validation showed that the expression of microRNA-376b-3p was downregulated by nearly 90 % in the livers of HFD-fed mice and by >50 % in free fatty acid-stimulated hepatocytes. Overexpression of microRNA-376b-3p markedly ameliorated hepatic lipid accumulation, which was attributable to an increase in fatty acid oxidation. Conversely, inhibition of miR-376b-3p exhibited the opposite effects. The luciferase reporter assay indicated that Fgfr1 is a direct target gene of miR-376b-3p. Fgfr1 intervention eliminated the effect of miR-376b-3p on the lipid oxidation pathway and hepatocyte steatosis, which suggests that miR-376b-3p regulates fatty acid oxidation by targeting Fgfr1 to influence NAFLD development. Significance miR-376b-3p was downregulated in NAFLD and has a novel regulatory role in lipid oxidation through a miR-376b-3p-Fgfr1-dependent mechanism. Thus, miR-376b-3p may serve as a potential diagnostic marker or therapeutic target for NAFLD.
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New neurons are generated in adult mammals. Adult hippocampal neurogenesis is considered to play an important role in cognition and mental health. The number and properties of newly born neurons are regulatable by a broad range of physiological and pathological conditions. To begin to understand the underlying cellular mechanisms and functional relevance of adult neurogenesis, many studies rely on quantification of adult-born neurons. However, lack of standardized methods to quantify new neurons is impeding research reproducibility across laboratories. Here, we review the importance of stereology, and propose why and how it should be applied to the study of adult neurogenesis.
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We present a consensus atlas of the human brain transcriptome in Alzheimer’s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington’s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
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In contextual fear conditioning, experimental subjects learn to associate a neutral context with an aversive stimulus and display fear responses to a context that predicts danger. Although the hippocampal–amygdala pathway has been implicated in the retrieval of contextual fear memory, the mechanism by which fear memory is encoded in this circuit has not been investigated. Here, we show that activity in the ventral CA1 (vCA1) hippocampal projections to the basal amygdala (BA), paired with aversive stimuli, contributes to encoding conditioned fear memory. Contextual fear conditioning induced selective strengthening of a subset of vCA1–BA synapses, which was prevented under anisomycin-induced retrograde amnesia. Moreover, a subpopulation of BA neurons receives stronger monosynaptic inputs from context-responding vCA1 neurons, whose activity was required for contextual fear learning and synaptic potentiation in the vCA1–BA pathway. Our study suggests that synaptic strengthening of vCA1 inputs conveying contextual information to a subset of BA neurons contributes to encoding adaptive fear memory for the threat-predictive context. Previous studies implicate the hippocampal–amygdala pathway in contextual fear conditioning, in which animals learn to associate a neutral context with an aversive stimulus and display fear responses to dangerous situations. Here the authors show that selective strengthening of hippocampal–amygdala pathway contributes to encoding adaptive fear memory for threat-predictive context.
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Over the last several years it has become clear that higher order assemblies on membranes, exemplified by signalosomes, are a paradigm for the regulation of many membrane signaling processes. We have recently combined two-color direct stochastic optical reconstruction microscopy (dSTORM) with the (Clus-DoC) algorithm that combines cluster detection and colocalization analysis to observe the organization of 5-lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) into higher order assemblies on the nuclear envelope of mast cells; these assemblies were linked to leukotriene (LT)C4 production. In this study we investigated whether higher order assemblies of 5-LO and FLAP included cytosolic phospholipase A2 (cPLA2) and were linked to LTB4 production in murine neutrophils. Using two- and three-color dSTORM supported by fluorescence lifetime imaging microscopy we identified higher order assemblies containing 40 molecules (median) [IQR: 23, 87] of 5-LO, and 53 molecules [62, 156] of FLAP monomer. 98 [18, 154] molecules of cPLA2 were clustered with 5-LO; and 77 [33, 114] molecules of cPLA2 were associated with FLAP. These assemblies were tightly linked to LTB4 formation. The activation-dependent close associations of cPLA2, FLAP and 5-LO in higher order assemblies on the nuclear envelope support a model in which arachidonic acid is generated by cPLA2 in apposition to FLAP, facilitating its transfer to 5-LO to initiate LT synthesis.
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Aging-related cellular and molecular processes including low-grade inflammation are major players in the pathogenesis of cardiovascular disease (CVD) and Alzheimer's disease (AD). Epidemiological studies report an independent interaction between the development of dementia and the incidence of CVD in several populations, suggesting the presence of overlapping molecular mechanisms. Accumulating experimental and clinical evidence suggests that amyloid-beta (Aβ) peptides may function as a link among aging, CVD, and AD. Aging-related vascular and cardiac deposition of Αβ induces tissue inflammation and organ dysfunction, both important components of the Alzheimer's disease amyloid hypothesis. In this review, the authors describe the determinants of Aβ metabolism, summarize the effects of Aβ on atherothrombosis and cardiac dysfunction, discuss the clinical value of Αβ1-40 in CVD prognosis and patient risk stratification, and present the therapeutic interventions that may alter Aβ metabolism in humans.
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Considerable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination. However, the intra- and extrahippocampal pathways that route contextual information to cortical and subcortical circuits to guide adaptive behavioral responses are poorly understood. Using terminal-specific optogenetic silencing in a contextual fear discrimination learning paradigm, we identify opposing roles for dorsal CA3-CA1 (dCA3-dCA1) projections and dorsal CA3-dorsolateral septum (dCA3-DLS) projections in calibrating fear responses to certain and ambiguous contextual threats, respectively. Ventral CA3-DLS (vCA3-DLS) projections suppress fear responses in both certain and ambiguous contexts, whereas ventral CA3-CA1 (vCA3-vCA1) projections promote fear responses in both these contexts. Lastly, using retrograde monosynaptic tracing, ex vivo electrophysiological recordings, and optogenetics, we identify a sparse population of DLS parvalbumin (PV) neurons as putative relays of dCA3-DLS projections to diverse subcortical circuits. Taken together, these studies illuminate how distinct dCA3 and vCA3 outputs calibrate contextual fear discrimination. : Besnard et al. show that dorsal and ventral hippocampal CA3 projections to CA1 and dorsolateral septum (DLS) play distinct roles in calibration of contextual fear discrimination. DLS parvalbumin inhibitory neurons receive monosynaptic dorsal CA3 inputs and modulate fear responses in a context-specific manner. Keywords: hippocampus, memory, contextual fear discrimination, dorsolateral septum, lateral septum, ventral hippocampus, dorsal hippocampus
A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases. Cell-extrinsic changes in the systemic environment, transported to the site of action by the blood, have recently been shown to contribute to brain ageing. In this Review, Pluvinage and Wyss-Coray discuss how circulating molecules in the blood modulate brain function in health, ageing and disease.
Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.