Genetic context controls early microglia-synaptic interactions in mouse models of Alzheimer’s disease

Abstract

ABSTRACTCommon features of Alzheimer’s 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/PS1mouse 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) andAPP/PS1yet a marked stability of spines across PWK mice. We further showed that synaptic changes depend on direct microglia-dendrite interactions in B6.APP/PS1but not PWK.APP/PS1mice. Collectively, these results demonstrate that microglia-dependent synaptic alterations in a specific AD-vulnerable projection pathway are differentially controlled by genetic context.