Convergent Transcriptomic and Genomic Evidence Supporting a Dysregulation of CXCL16 and CCL5 in Alzheimer's Disease

author:	Li, X (Li, Xiao); Zhang, DF (Zhang, Deng-Feng); Bi, R (Bi, Rui); Tan, LW (Tan, Li-Wen); Chen, XG (Chen, Xiaogang); Xu, M (Xu, Min); Yao, YG (Yao, Yong-Gang)
Abstract:	Background Neuroinflammatory factors, especially chemokines, have been widely reported to be involved in the pathogenesis of Alzheimer's disease (AD). It is unclear how chemokines are altered in AD, and whether dysregulation of chemokines is the cause, or the consequence, of the disease.MethodsWe initially screened the transcriptomic profiles of chemokines from publicly available datasets of brain tissues of AD patients and mouse models. Expression alteration of chemokines in the blood from AD patients was also measured to explore whether any chemokine might be used as a potential biomarker for AD. We further analyzed the association between the coding variants of chemokine genes and genetic susceptibility of AD by targeted sequencing of a Han Chinese case-control cohort. Mendelian randomization (MR) was performed to infer the causal association of chemokine dysregulation with AD development.ResultsThree chemokine genes (CCL5, CXCL1, and CXCL16) were consistently upregulated in brain tissues from AD patients and the mouse models and were positively correlated with A beta and tau pathology in AD mice. Peripheral blood mRNA expression of CXCL16 was upregulated in mild cognitive impairment (MCI) and AD patients, indicating the potential of CXCL16 as a biomarker for AD development. None of the coding variants within any chemokine gene conferred a genetic risk to AD. MR analysis confirmed a causal role of CCL5 dysregulation in AD mediated by trans-regulatory variants.ConclusionsIn summary, we have provided transcriptomic and genomic evidence supporting an active role of dysregulated CXCL16 and CCL5 during AD development
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PubYear:	2023
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Unit code:	152453
Publication name:	Alzheimers Research & Therapy
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Paper source:	https://alzres.biomedcentral.com/articles/10.1186/s13195-022-01159-5
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