Hewes, A. A. | Search bioRxiv

bioRxiv2023

Genetic context controls early microglia-synaptic interactions in mouse models of Alzheimers disease

Common features of Alzheimers disease (AD) include amyloid pathology, microglia activation and synaptic dysfunction, however, the causal relationships amongst them remains unclear. Further, human data suggest susceptibility and resilience to AD neuropathology is controlled by genetic context, a factor underexplored in mouse models. To this end, we leveraged viral strategies to label an AD-vulnerable neuronal circuit in CA1 dendrites projecting to the frontal cortex in genetically diverse C57BL/6J (B6) and PWK/PhJ (PWK) APP/PS1 mouse strains and used PLX5622 to non-invasively deplete brain microglia. Reconstructions of labeled neurons revealed microglia-dependent changes in dendritic spine density and morphology in B6 wild-type (WT) and APP/PS1 yet a marked stability of spines across PWK mice. We further showed that synaptic changes depend on direct microglia-dendrite interactions in B6.APP/PS1 but not PWK.APP/PS1 mice. Collectively, these results demonstrate that microglia-dependent synaptic alterations in a specific AD-vulnerable projection pathway are differentially controlled by genetic context.

neuroscience↗

bioRxiv2022

APOEϵ4 and exercise interact to influence systemic and cerebral risk factors for dementia

INTRODUCTIONAPOE{varepsilon}4 is the strongest genetic risk factor for Alzheimers disease and related dementias (ADRDs) affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention, and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and APOE{varepsilon}4 affect similar processes on the body and brain. While both APOE{varepsilon}4, and exercise have been studied extensively, their interactive effects are not well understood. METHODSTo address this, male and female APOE{varepsilon}3/{varepsilon}3, APOE{varepsilon}3/{varepsilon}4 and APOE{varepsilon}4/{varepsilon}4 mice ran voluntarily from wean (1mo) to midlife (12mo). Longitudinal and cross-sectional phenotyping was performed on the periphery and the brain, on markers of risk for dementia such as weight, body composition, circulating cholesterol composition, activities of daily living, energy expenditure, and cortical and hippocampal transcriptional profiling. RESULTSData revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum LDL concentration dependent on APOE genotype. Additionally, murine activities of daily living and energy expenditure were significantly influenced by an interaction between APOE genotype and running in both sexes. Transcriptional profiling of the cortex and hippocampus predicted that APOE genotype and running interact to affect numerous biological processes including vascular integrity, synaptic/neuronal health, cell motility, and mitochondrial metabolism, in a sex-specific manner. DISCUSSIONThese data provide compelling evidence that APOE genotype should be considered for population-based strategies that incorporate exercise to prevent ADRDs.

genetics↗