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Review
. 2022 Mar 3;8(1):3-14.
doi: 10.1002/ibra.12026. eCollection 2022 Spring.

Research progress of the CXCR4 mechanism in Alzheimer's disease

Qiu-Lin Wang  1 , Chang-Le Fang  2 , Xue-Yan Huang  3 , Lu-Lu Xue  4
Affiliations
Review

Research progress of the CXCR4 mechanism in Alzheimer's disease

Qiu-Lin Wang et al. Ibrain. .

Abstract

Alzheimer's disease (AD) is a degenerative brain disease with complex clinical manifestations and pathogeneses such as abnormal deposition of beta-amyloid protein and inflammation caused by the excessive activation of microglia. CXC motif chemokine receptor type 4 (CXCR4) is a type of G protein-coupled receptor that binds to CXC motif ligand 12 (CXCL12) to activate downstream signaling pathways, such as the Janus kinase/signal transducer and activator of transcription and the renin-angiotensin system (Ras)/RAF proto-oncogene serine (Raf)/mitogen-activated protein kinase/extracellular-regulated protein kinase; most of these signaling pathways are involved in inflammatory responses. CXCR4 is highly expressed in the microglia and astrocytes; this might be one of the important causes of inflammation caused by microglia and astrocytes. In this review, we summarize the mechanism and therapeutics of AD, the structures of CXCR4 and the CXCL12 ligand, and the mechanisms of CXCR4/CXCL12 that are involved in the occurrence and development of AD. The possible treatment of AD through microglia and astrocytes is also discussed, with the aim of providing a new method for the treatment of AD.

Keywords: Alzheimer's disease; CXCL12; CXCR4; astrocytes; microglia.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The pathogenesis of AD. Because of increasing insulin levels in the brain, the insulin signaling pathway is blocked, and then the production of Aβ is increased and the clearance of Aβ is decreased, leading to the accumulation of Aβ in the brain. Aβ can damage synapses, lead to signal transmission obstruction, damage neurons, and activate microglia, which can produce inflammation. A decrease in the number of neurons leads to a decline in cognitive function. Activated microglia can phagocytize Aβ. Aβ, β amyloid AD, Alzheimer's disease [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
CXCL12/CXCR4 participating signaling pathways. AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; CXCL12, CXC motif ligand 12; CXCR4, chemokine receptor type 4; DAG, diglycerol; IP3, inositol 1, 4, 5‐triphosphate; JAK, Janus kinase; MAPK, mitogen‐associated protein kinase; NF‐κB, nuclear factor kappa B; PI3K, phosphatidylinosine 3 kinase; PKA, protein kinase A; PKC, protein kinase C; PIP2, phosphatidylinositol 4, 5‐diphosphate; STAT, signal transducer and activator of transcription [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
B‐cell migration. Decrease of CXCR4 caused the migration of B cells from the bone marrow to peripheral blood and an increase of anti‐Aβ antibody, which crossed the blood–brain barrier and entered the cerebrospinal fluid. Antibodies entering cerebrospinal fluid can clear Aβ and activate microglia, further increasing the clearance of Aβ. Aβ, β amyloid; CXCR4, chemokine receptor type 4 [Color figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
Mind map Text flow chart. AD, Alzheimer's disease; CXCR4, chemokine receptor type 4 [Color figure can be viewed at wileyonlinelibrary.com]
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