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Review
. 2023 Apr 21;12(8):1207.
doi: 10.3390/cells12081207.

The Functions and Phenotypes of Microglia in Alzheimer's Disease

Risako Fujikawa  1 , Makoto Tsuda  1   2
Affiliations
Review

The Functions and Phenotypes of Microglia in Alzheimer's Disease

Risako Fujikawa et al. Cells. .

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, but therapeutic strategies to slow down AD pathology and symptoms have not yet been successful. While attention has been focused on neurodegeneration in AD pathogenesis, recent decades have provided evidence of the importance of microglia, and resident immune cells in the central nervous system. In addition, new technologies, including single-cell RNA sequencing, have revealed heterogeneous cell states of microglia in AD. In this review, we systematically summarize the microglial response to amyloid-β and tau tangles, and the risk factor genes expressed in microglia. Furthermore, we discuss the characteristics of protective microglia that appear during AD pathology and the relationship between AD and microglia-induced inflammation during chronic pain. Understanding the diverse roles of microglia will help identify new therapeutic strategies for AD.

Keywords: Alzheimer’s disease; ApoE; CD11c; DAMs; TREM2; amyloid beta; brain; microglia; monocyte; pain; spinal cord; tau.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Various responses of microglia to amyloid β. Cytokine release: Aβ directly stimulates TNF-α production in microglia by activating the transcription factor NF-κB. TNF-α increases the expression of β- and γ-secretase which generate Aβ from APP.
Figure 2
Figure 2
Phagocytosis: The CX3CL1/CX3CR1 axis plays a key role in the phagocytosis of tau by microglia and is affected as AD progresses. S396 Tau phosphorylation decreases the binding affinity of this protein to CX3CR1.
Figure 3
Figure 3
DAMs are activated sequentially by two steps. Schematic illustration showing the two steps by which microglia switch from homeostatic to DAMs. The first step: TREM2-independent downregulation of homeostatic markers such as P2RY12, CX3CR1, and Tmem119. The second step: TREM2-dependent overexpression of genes involved in phagocytosis and lipid metabolism. Arrows indicate up- or down-regulation of the gene.
See this image and copyright information in PMC

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