SEX SPECIFIC EFFECTS OF EXERCISE ON BEHAVIOUR, NEUROGENESIS, AND THE GUT MICROBIOME IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by increased amyloid-beta plaques, tau protein aggregates, and reduced adult hippocampal neurogenesis (AHN). Recent research reports a causal connection between the gut microbiome and AD symptomatology. Building on our findings that the microbiome is required for exercise-induced enhancement of AHN and memory, we examined how exercise affects 1) behaviour, 2) AD-related neuropathology, 3) gut microbiome composition/function, and 4) whether these effects are sex-specific in the 5xFAD mouse model of AD. Female and male 5xFAD mice (5-6 months) were group-housed with or without access to running wheels. The Open Field Test (OFT), for anxiety-like behaviour, and Delayed Non-Matching-to-Place Task (DNMP), for pattern separation, were conducted 4 weeks later. Mice were euthanized 6-9 weeks after the exercise intervention began. Amyloid plaques were quantified by light sheet microscopy (congo red) and neurogenesis (DCX positive cells) assessed by immunofluorescence. Caecal microbiome was analyzed by 16S rRNA sequencing and short chain fatty acids by targeted metabolomics. Exercise increased DNMP percentage of correct choice in males, indicating improved pattern separation, and increased OFT center entries in females, indicating reduced anxiety-like behaviour. Exercise decreased plaque density and increased AHN in both sexes, but only males had increased AHN in the dorsal hippocampus, which plays a role in spatial memory. Exercise decreased the microbial genus Akkermansia and its metabolite propanoic acid in females, a pathway previously linked to AD-related improvements. Thus, biological sex should be considered when examining the potential of exercise as a microbial-mediated preventative strategy in AD.