Retromer pathways can regulate AD‐associated neuronal and microglial phenotypes

Abstract

AbstractThe relationship between retromer‐dependent pathways in neurons and neighboring glial remains unknown. To address this question, we turn to a genetic mouse model where the retromer core protein VPS35 is depleted in hippocampal neurons, and then we replete VPS35 using an optimized viral vector protocol. The VPS35 depletion‐repletion studies strengthen the causal link between the neuronal retromer and AD‐associated neuronal phenotypes, including the acceleration of amyloid precursor protein cleavage and the loss of synaptic glutamate receptors. More interestingly, the studies show that the neuronal retromer can regulate a distinct, dystrophic, microglia morphology, phenotypic of hippocampal microglia in AD. Finally, the neuronal and, in part, the glial responses to VPS35 depletion were found to occur independent of tau. Future studies are required to determine the mechanisms by which retromer‐dependent dysfunction in neurons provokes neighboring microglia.