Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is the most common form of dementia that is initiated by extracellular plaque deposition and intraneuronal hyperphosphorylated tau aggregates. Reactive astrocytosis and microgliosis are secondary cellular responses to pathology that have gained increasing attention. Variants of the microglia receptor TREM2 increase AD risk and activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD. To investigate global transcriptomic changes during AD pathology, we surveyed gene expression changes associated with AD pathology and TREM2 in Ab-driven 5XFAD mouse model and human AD by single nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a novel Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.