Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?

Abstract

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated microglia (DAM); additional reactive microglial populations have been reported in other models of neurodegeneration and neuroinflammation. We review all of these microglial signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, and proliferating microglia. We propose that all reported microglia populations are either just one or a combination, depending on the clustering strategy applied and the disease model. We further review single-nucleus RNA sequencing (snRNA-seq) data from human AD specimens and discuss reasons for parallels and discrepancies between human and mouse transcriptional profiles. Finally, we outline future directions for delineating the microglial impact in AD pathogenesis.

Figure 1.

Temporal appearance of microglial subsets with activated signatures in mouse life span. Signatures of proliferative region–associated microglia (PAM) and axon tract–associated microglia (ATM) transiently appear in early stages of postnatal development. The dashed line above ATM and PAM indicates the possibility that ATM and PAM may belong to the same wave of microglia activation. Moreover, microglia with DAM/MHC/IFN-I activation signatures slowly increase with aging, a process that is accelerated in models of neurodegeneration.