Unraveling the genetic underpinnings of mitochondrial traits and associated circulating inflammatory proteins in Alzheimer's disease: Mitochondrial HtrA2-T cell CD5 negative axis.

IF 3.4 3区 医学 Q2 NEUROSCIENCES
Yixi Wang, Zhuokai Wu, Yiheng Zheng, Haimeng Wang, Bin Cheng, Juan Xia
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Abstract

BackgroundPrevious studies with limited sample sizes have indicated a link between mitochondrial traits, inflammatory proteins, and Alzheimer's disease. The exact causality and their mediation relationships remain unclear.ObjectiveOur study aimed to delve into the genetic underpinnings of mitochondrial function and circulating inflammatory proteins in the pathogenesis of Alzheimer's disease.MethodsWe leveraged aggregated data from the largest genome-wide association study, including 69 mitochondrial traits, 91 circulating inflammatory proteins, and Alzheimer's disease. Bidirectional mendelian randomization (MR) analyses were performed to investigate their primary causal relationships. Thereafter a two-step MR mediation analysis was utilized to clarify the modulating effects of inflammatory proteins on mitochondria and Alzheimer's disease.ResultsOur study identified mitochondrial phenylalanine-tRNA ligase and 4-hydroxy-2-oxoglutarate aldolase as risk factors for Alzheimer's disease, and serine protease HtrA2 and carbonic anhydrase 5A as protective factors against Alzheimer's disease. Four inflammatory proteins (T-cell surface glycoprotein CD5, C-X-C motif chemokine 11, TGF-α, and TNF-related apoptosis-inducing ligand) played protective roles against Alzheimer's disease. Axin-1 and IL-6 increased the risk of Alzheimer's disease. Furthermore, T-cell surface glycoprotein CD5 was found to be a significant mediator between mitochondrial serine protease HTRA2 and Alzheimer's disease with the two-step MR method, accounting for 10.83% of the total effect.ConclusionsOur study emphasized mitochondrial HtrA2-T cell CD5 as a negative axis in Alzheimer's disease, offering novel perspectives on its etiology, pathogenesis, and treatment.

揭示阿尔茨海默病中线粒体特征和相关循环炎症蛋白的遗传基础:线粒体HtrA2-T细胞CD5负轴
之前有限样本量的研究表明,线粒体特征、炎症蛋白和阿尔茨海默病之间存在联系。确切的因果关系及其调解关系尚不清楚。目的探讨线粒体功能和循环炎症蛋白在阿尔茨海默病发病机制中的遗传基础。方法:我们利用了最大的全基因组关联研究的汇总数据,包括69个线粒体特征,91个循环炎症蛋白和阿尔茨海默病。进行双向孟德尔随机化(MR)分析以调查其主要因果关系。随后,利用两步磁共振介导分析来阐明炎症蛋白对线粒体和阿尔茨海默病的调节作用。结果线粒体苯丙氨酸- trna连接酶和4-羟基-2-氧葡萄糖酸醛缩酶是阿尔茨海默病的危险因素,丝氨酸蛋白酶HtrA2和碳酸酐酶5A是阿尔茨海默病的保护因素。四种炎症蛋白(t细胞表面糖蛋白CD5、C-X-C基序趋化因子11、TGF-α和tnf相关的凋亡诱导配体)对阿尔茨海默病具有保护作用。Axin-1和IL-6增加阿尔茨海默病的风险。此外,两步MR方法发现t细胞表面糖蛋白CD5是线粒体丝氨酸蛋白酶HTRA2与阿尔茨海默病之间的重要中介,占总效应的10.83%。结论我们的研究强调了线粒体HtrA2-T细胞CD5在阿尔茨海默病中的负轴作用,为其病因、发病机制和治疗提供了新的视角。
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来源期刊
Journal of Alzheimer's Disease
Journal of Alzheimer's Disease 医学-神经科学
CiteScore
6.40
自引率
7.50%
发文量
1327
审稿时长
2 months
期刊介绍: The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.
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