Microglia show distinct tau associated subpopulations along tau spreading in human Alzheimer’s disease

Abstract

AbstractBackgroundIn Alzheimer’s disease (AD) progression, amyloid beta load uniformly increases across the brain cortex, while neurofibrillary tangles progressively spread in a stereotypical pattern from entorhinal to visual cortex. AD is known to have a strong genetic link to microglia and recently, expression profiling at single cell resolution has identified disease‐associated microglia populations with differential amyloid‐beta vs. tau pathology association in human AD brain. However, prior human studies focusing on microglia included a limited number of donors and/or cells per donor, and how microglial transcriptomes change with progression of tau pathology remains largely unknown.MethodUsing single nuclei RNA sequencing, we profiled 337,512 microglia from 32 donors across 4 pathology groups (no to severe pathology) and five brain regions along the tau spreading pathway (entorhinal cortex, Brodmann Area 20, Brodmann Area 46, secondary visual cortex, and primary visual cortex) to investigate their cellular heterogeneity as a function of disease progression. Phospho‐Tau231 and HT7‐HT7 aggregated tau levels of adjacent tissue were assessed for quantification of tau pathology.ResultWe confirmed previously described microglial populations across all profiled regions and identified cluster associations with tau levels, which mirrored the expected stereotypical progression across brain regions. Integrative analysis showed high similarity of microglia subtypes across regions, but interestingly also revealed entorhinal cortex and late tau pathology enriched clusters. Genes upregulated in early vs. late tau‐affected regions at severe pathology stage, but not in healthy brain, were found to be enriched in DNA repair and replication processes as well as immune response activation, while downregulated genes corresponded to glial cell differentiation and gliogenesis.ConclusionThis study constitutes a high‐quality resource of microglia phenotypes in a previously unmet sample size with regard to both donors and cells per donor, well characterized by quantitative readouts for tau pathology association across tau spreading regions. We foresee this study will contribute to a better understanding of how microglial phenotypes can be targeted during the progression of tau pathology in AD, while further work is required to distinguish causality from consequence.