Abstract
BackgroundIncreased physical exercise improves cognitive function and reduces pathology associated with Alzheimer’s disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state.MethodsMale 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (Aβ) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice.ResultsLong-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, Aβ plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from Aβ plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95.ConclusionsVoluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.
Highlights
Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer’s disease (AD)
Voluntary physical exercise selectively affected the GFAPpositive population of astrocytes Given the exercise-induced increase of glial fibrillary acidic protein (GFAP) immunoreactivity in 5xFAD brains, we investigated whether other astrocytic markers such as s100 calcium binding protein β (S100β), glutamine synthetase (GS), and Aldehyde dehydrogenase 1 family (ALDH1L1) were affected by voluntary physical exercise in the hippocampus of 5xFAD mice
The findings of our study suggest that voluntary exercise partially improves synaptic function by increasing Postsynaptic density 95 (PSD-95) and brain-derived neurotrophic factor (BDNF) in the hippocampi of AD mice with no effect on adult neurogenesis or neuronal survival
Summary
Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer’s disease (AD). Because it is known that a sedentary lifestyle is associated with impaired cognitive function and AD [2], one possible way to ameliorate AD pathology is regular physical exercise. Physical exercise has been shown to improve learning and memory by increasing long-term potentiation (LTP) and neurogenesis [4]. Physical exercise is associated with structural and functional changes in the brain, promoting neuronal plasticity through increasing the levels of neurotropic and growth factors such as brain-derived neurotrophic factor (BDNF) [5]. Given that glial cells regulate many aspects of neuronal function and synaptic plasticity, the effects of physical exercise on glial cells may have broad implications for cognitive function, learning, and memory [6]
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