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.
Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
Disclosures: M. Colonna reported grants from NIH during the conduct of the study and received research support from Alector, Amgen, Ono, and Pfizer; in addition, M. Colonna is a scientific advisory board member of Vigil and NGMBio, is a consultant for Cell Signaling Technologies, and has a patent to TREM2 pending. No other disclosures were reported.
- Award Group:
- Funder(s): National Institutes of Health
- Award Ids(s): RF1 AG051485,R21 AG059176,RF1 AG059082
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Yun Chen, Marco Colonna; Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?. J Exp Med 6 September 2021; 218 (9): e20202717. doi: https://doi.org/10.1084/jem.20202717
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