Subtle Alterations in Hippocampal Neuronal Activity Coincide With Early Sex‐Specific Differences in Amyloidosis and Microglia in a Pre‐Symptomatic Mouse Model of Alzheimer‐Like Pathology

Growing evidence highlights sex-related differences in the pathogenesis of Alzheimer's disease (AD). Yet, early impact of sex on neuronal activity and microglia in the hippocampus, a main site of memory formation and one of the most vulnerable brain areas in AD, remains poorly understood. We thus assessed these issues by using APPPS1 mouse model of AD-like amyloid pathology at a pre-symptomatic stage (5-6 months). Our electrophysiological data point to opposite alterations in hippocampal CA1 neurons' basal glutamatergic neurotransmission and response to excitatory inputs between male and female APPPS1 mice. These complex changes in neuronal activity are likely to precede plasticity impairments, which do not yet translate into sexual dimorphism of Long-Term Potentiation (LTP) at the studied age. Alteration in synaptic transmission in males coincides with an increased number and coverage of microglia, together with increased plaque coverage, as compared to the female hippocampus. Such increased microgliosis in males is accompanied by complex sex-related differences in the expression of specific transcriptomic markers Disease-Associated Microglia (DAM)/Microglial neurodegenerative phenotype (MGnD), whereas homeostatic (M0) markers were unaffected. Our data show for the first time that subtle alterations in hippocampal neuronal activity coincide with early sex-related differences in amyloidosis and microglia already at the pre-symptomatic stage of AD-like pathology.