Abstract
Microglia are resident immune cells in the central nervous system and play critical roles in brain immunity, development, and homeostasis. The pathology of Alzheimer’s disease (AD) triggers activation of microglia. Microglia express many AD risk genes, suggesting that their response to AD pathology can affect disease progression. Microglia have long been considered a homogenous cell population. The diversity of microglia has gained great interest in recent years due to the emergence of novel single-cell technologies, such as single-cell/nucleus RNA sequencing and single-cell mass cytometry by time-of-flight. This review summarizes the current knowledge about the diversity/heterogeneity of microglia and distinct microglia states in the brain of both AD mouse models and patients, as revealed by single-cell technologies. It also discusses the future developments for application of single-cell technologies and the integration of these technologies with functional studies to further dissect microglia biology in AD. Defining the functional correlates of distinct microglia states will shed new light on the pathological roles of microglia and might uncover new relevant therapeutic targets for AD.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disease with progressive memory decline and cognitive dysfunction, which is pathologically characterized by extracellular deposition of β-amyloid (Aβ) and intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau, accompanied by neuroinflammation, neuronal, and synapse loss (Long and Holtzman, 2019; van der Kant et al, 2020; Knopman et al, 2021)
Many of AD risk genes, such as triggering receptor expressed in myeloid cells 2 (TREM2), complement receptor 1
DAM (Apoe; Axl, Csf1, Clec7a, Cst7, Gpnmb, Igf1, Itgax, Spp1, Trem2; Cx3cr1, P2ry12, Tmem119) DAM like subset; reactive microglia subsets with IFN I and II response genes DAM-like (CD11c, CD14, CD86, CD44, programmed death ligand 1 (PDL1); Cx3cr1, MerTK and Siglec-H) activated response microglia (ARM) (H2-Ab1 and Cd74; Dkk2, Gpnmb and Spp1) and IFN response microglia (IRM) ARM enriched for AD risk genes snRNA-seq Cortex and hippocampus scRNA-seq scRNA-seq scRNA-seq
Summary
The predominant resident immune cells within the central nervous system (CNS), are capable of performing various functions in the brain under both homeostatic and disease conditions (Hansen et al, 2018; Tejera and Heneka, 2019; Bartels et al, 2020; Leng and Edison, 2021). AD Microglia at Single-Cell Resolution (CR1), cluster of differentiation 33 (CD33) and inositol polyphosphate-5-phosphatase (INPP5D), are preferentially expressed in microglia (Shi and Holtzman, 2018; Verheijen and Sleegers, 2018; Tejera and Heneka, 2019; Hashemiaghdam and Mroczek, 2020; Leng and Edison, 2021; Streit et al, 2021) Functional studies of these AD risk genes have been instrumental in establishing roles of microglia in AD pathogenesis and progression (Shi and Holtzman, 2018; Ulland and Colonna, 2018; Sierksma et al, 2020; Bhattacherjee et al, 2021; Chen and Colonna, 2021; Lee et al, 2021). Using massively parallel scRNA-seq (MARS-seq), Keren-Shaul et al (2017) mapped the immune cells (CD45+) in mouse brains and identified microglia clusters with distinct gene expression profiles, that were referred to as neurodegenerative disease-associated microglia (DAM), in the cortical regions of 5XFAD
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