Late‐life physical activity relates to brain tissue synaptic integrity markers in older adults

Casaletto, Kaitlin B.; Ramos-Miguel, Alfredo; VandeBunte, Anna; Memel, Molly; Buchman, Aron S.; Bennett, David A.; Honer, William G.

doi:10.1002/alz.12530

Cited by 37 publications

(25 citation statements)

References 51 publications

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“…Synaptic protein. Synaptic integrity was quantified as average levels of six synaptic proteins previously shown to demonstrate significant relationships with physical activity (SNAP-25, complexin-I, synaptophysin, synpatotagmin-1, syntaxin, VAMP) (Casaletto et al, 2021).…”

Section: Postmortem Indicesmentioning

confidence: 99%

“…We monitored objective activity levels via accelerometerbased actigraphy in older adults during life who completed autopsy with brain tissue quantified for immunohistochemistrybased microglial activation markers (anti-human HLA-DP-DQ-DR, plus morphology staging) as part of the Rush Memory and Aging Project (MAP). Prior MAP studies demonstrate that actigraphybased physical activity is associated with better cognitive trajectories, reduced incidence of Alzheimer's dementia (Buchman et al, 2012(Buchman et al, , 2018, and higher levels of synaptic proteins in brain tissue (Casaletto et al, 2021). We aimed to characterize the relationship between late life physical activity and markers of microglial activation in MAP participants, including regional and pathology-specific effects.…”

Section: Introductionmentioning

confidence: 99%

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Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults

et al. 2021

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Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ;30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from .40% in adults with high AD burden, but ,10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states.

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Section: Postmortem Indicesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults

et al. 2021

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“…Synapse-related genes are extensively downregulated in multiple brain regions in both aging and AD [ 72 ]. Furthermore, greater physical activity is associated with higher levels of synaptic integrity markers, including synaptophysin, synaptotagmin-1, vesicle-associated membrane proteins, syntaxin, and complexin-I, in the brain of older adults [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

Physical Activity Rewires the Human Brain against Neurodegeneration

Santiago¹,

Quinn

Potashkin

2022

IJMS

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Physical activity may offset cognitive decline and dementia, but the molecular mechanisms by which it promotes neuroprotection remain elusive. In the absence of disease-modifying therapies, understanding the molecular effects of physical activity in the brain may be useful for identifying novel targets for disease management. Here we employed several bioinformatic methods to dissect the molecular underpinnings of physical activity in brain health. Network analysis identified ‘switch genes’ associated with drastic hippocampal transcriptional changes in aged cognitively intact individuals. Switch genes are key genes associated with dramatic transcriptional changes and thus may play a fundamental role in disease pathogenesis. Switch genes are associated with protein processing pathways and the metabolic control of glucose, lipids, and fatty acids. Correlation analysis showed that transcriptional patterns associated with physical activity significantly overlapped and negatively correlated with those of neurodegenerative diseases. Functional analysis revealed that physical activity might confer neuroprotection in Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD) diseases via the upregulation of synaptic signaling pathways. In contrast, in frontotemporal dementia (FTD) its effects are mediated by restoring mitochondrial function and energy precursors. Additionally, physical activity is associated with the downregulation of genes involved in inflammation in AD, neurogenesis in FTD, regulation of growth and transcriptional repression in PD, and glial cell differentiation in HD. Collectively, these findings suggest that physical activity directs transcriptional changes in the brain through different pathways across the broad spectrum of neurodegenerative diseases. These results provide new evidence on the unique and shared mechanisms between physical activity and neurodegenerative diseases.

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“…A meta-analysis across 12 cohorts including thousands of participants also concluded that physical activity significantly protected against cognitive decline, even at low to moderate levels (Sofi et al, 2011). A recent study found that late-life physical activity was associated with higher presynaptic protein levels, known to positively affect cognition (Casaletto et al, 2021). Indeed, recent meta-analyses of randomized controlled trials using physical activity interventions reveal notable protective effects for dementia risk (Beckett, Ardern, & Rotondi, 2015; Xu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Associations between physical activity and cognitive dysfunction in older companion dogs: Results from the Dog Aging Project

Bray

Raichlen

Forsyth

et al. 2022

Preprint

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Canine Cognitive Dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer’s disease. Given that physical activity is believed to reduce risk of Alzheimer’s disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity—with several important covariates—as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = -0.10, 95% CI: -0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = -0.07, 95% CI: -0.09 to -0.05, p <0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p <0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer’s disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical-activity interventions.

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Late‐life physical activity relates to brain tissue synaptic integrity markers in older adults

Cited by 37 publications

References 51 publications

Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults

Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults

Physical Activity Rewires the Human Brain against Neurodegeneration

Associations between physical activity and cognitive dysfunction in older companion dogs: Results from the Dog Aging Project

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