Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Oct 20;82(11):894-900.
doi: 10.1093/jnen/nlad071.

The intricate role of CCL5/CCR5 axis in Alzheimer disease

Weijiang Ma  1 , Aihua Liu  1   2 , Xinya Wu  1 , Li Gao  1 , Jingjing Chen  1 , Hanxin Wu  1 , Meixiao Liu  1 , Yuxin Fan  1 , Li Peng  1 , Jiaru Yang  1 , Jing Kong  1 , Bingxue Li  1 , Zhenhua Ji  1 , Yan Dong  1 , Suyi Luo  1 , Jieqin Song  1 , Fukai Bao  1   2
Affiliations
Review

The intricate role of CCL5/CCR5 axis in Alzheimer disease

Weijiang Ma et al. J Neuropathol Exp Neurol. .

Abstract

The morbidity and mortality associated with Alzheimer disease (AD), one of the most common neurodegenerative diseases, are increasing each year. Although both amyloid β and tau proteins are known to be involved in AD pathology, their detailed functions in the pathogenesis of the disease are not fully understood. There is increasing evidence that neuroinflammation contributes to the development and progression of AD, with astrocytes, microglia, and the cytokines and chemokines they secrete acting coordinately in these processes. Signaling involving chemokine (C-C motif) ligand 5 (CCL5) and its main receptor C-C chemokine receptor 5 (CCR5) plays an important role in normal physiologic processes as well as pathologic conditions such as neurodegeneration. In recent years, many studies have shown that the CCL5/CCR5 axis plays a major effect in the pathogenesis of AD, but there are also a few studies that contradict this. In short, the role of CCL5/CCR5 axis in the pathogenesis of AD is still intricate. This review summarizes the structure, distribution, physiologic functions of the CCL5/CCR5 axis, and the progress in understanding its involvement in the pathogenesis of AD.

Keywords: Alzheimer disease; Axis; CCL5; CCR5; Neuroinflammation.

PubMed Disclaimer

Conflict of interest statement

The authors have no duality or conflicts of interest to declare.

Figures

Figure 1.
Figure 1.
CCL5/CCR5 signaling pathway. CCR5 is a 7-transmembrane G protein-coupled receptor with 3 extracellular loops and 3 intracellular loops. The disulfide bonds formed by 4 cysteine residues in the extracellular domain are vital for stabilizing the extracellular structure. Three cysteine residues on the carboxyl terminal domain can anchor the tail to the membrane. DRYLAVHA sequence on the second intracellular loop can interact with G protein. Following CCL5 binding to CCR5, G protein dissociates into the αi and βγ subunits; the former inhibits adenylate cyclase (AC), whereas the latter activates phospholipase Cβ (PLCβ) and phosphatidylinositol 3 kinase (PI-3K). The following mediators are then activated in turn: diacylglycol (DAG), protein kinase C (PKC), inositol-1,4,5-triphosphate (IP3), intracellular Ca2+, calcineurin (CaN), nuclear factor of activated T cells (NFAT), extracellular signal regulated kinase 1 and 2 (ERK1/2), p38, c-Jun N-terminal kinase (JNK), protein kinase B (PKB/Akt), and Rho GTPases, which eventually affect cell migration, survival, cytoskeleton rearrangement, cell polarization, and T-cell proliferation.
Figure 2.
Figure 2.
Mechanisms of the CCL5/CCR5 axis in the pathogenesis of AD. In patients with AD, Aβ can upregulate CCL5 and CCR5; the resting microglia and astrocytes are transformed into the A1 and M1 phenotypes, and they secrete pro-inflammatory cytokines. Aβ deposition in the brain leads to immune activation and production of antibodies. Interaction of Aβ and receptor for advanced glycation endproducts (RAGE) expressed by cells of the blood-brain barrier (BBB) can promote CCR5 expression, resulting in the penetration of MIP-1-expressing T cells through tight junctions of the BBB. There is crosstalk between T cells and microglia, microglia act as antigen-presenting cells to present Aβ to T cells, which in turn induce microglia differentiation. With the development of AD, neurons eventually die.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Jia L, Du Y, Chu L, et al.; COAST Group. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: A cross-sectional study. Lancet Public Health 2020;5:e661–71 - PubMed
    1. Watermeyer T, Calia C.. Neuropsychological assessment in preclinical and prodromal Alzheimer disease: A global perspective. J Glob Health 2019;9:010317. - PMC - PubMed
    1. Hugo J, Ganguli M.. Dementia and cognitive impairment: Epidemiology, diagnosis, and treatment. Clin Geriatr Med 2014;30:421–42 - PMC - PubMed
    1. Braak H, Braak E.. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239–59 - PubMed
    1. Webers A, Heneka MT, Gleeson PA.. The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer’s disease. Immunol Cell Biol 2020;98:28–41 - PubMed

Publication types