White matter associated microglia in Alzheimer’s disease

Abstract

AbstractBackgroundWhite matter is composed of mostly myelinated axons that connect neurons from different brain regions into functional circuits. Aging results in both grey and white matter degeneration, but the specific microglial responses to the damage is unknown. Strikingly, in Alzheimer’s disease white matter alterations occur early in the disease course. Here, we analyzed microglia responses in the white matter in aging rodents and models of Alzheimer’s disease.MethodWe dissociated grey and white matter tracts and isolated microglia from young and aged mice and performed single cell RNA sequencing. To compare aging and neurodegeneration effects on microglia, we isolated microglia from a transgenic Alzheimer’s disease mouse model, and to study signaling pathways we included aged Trem2 and Apoe knockout mice into the analysis. Validation and characterization of the phenotypes occurred by in situ hybridization, immunohistochemistry, correlated light and electron microscopy.ResultsUsing single‐cell RNA sequencing from white and grey matter separately, we identified white matter associated microglia, which shared distinct parts of the disease‐associated microglia (DAM) gene signature. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin, depending on Trem2 signaling. In the aged brain, white matter associated microglia form independently of ApoE, which is in contrast to mouse models of Alzheimer’s disease, in which microglia with white matter associated microglia gene signature are generated prematurely and in an ApoE‐dependent pathway similar to DAM.ConclusionWe propose that white matter associated microglia represent a protective metabolic response, required to clear the increasing amounts of myelin debris that accumulate during aging and AD. We speculate that premature formation of white matter associated microglia in AD may contribute to the development of neurodegenerative disease, possibly by attrition of microglia function leading to accumulation of toxic protein or lipid species within the brain.