血液胰蛋白酶对阿尔茨海默病风险及相关病理生物标志物的影响:观察性队列和孟德尔随机研究的结果

X.-H. Qian, G.-Y. Ding, S.-Y. Chen, Xiao-li Liu, Miao Zhang, Hui-dong Tang
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引用次数: 0

摘要

背景阿尔茨海默病(AD)是痴呆症的主要类型,涉及复杂的病理生理过程,包括溶酶体功能异常。胰蛋白酶是内溶酶体系统中负责降解各种底物的主要蛋白酶。本研究采用孟德尔随机法(Mendelian randomization,MR)研究血液中的胰蛋白酶与AD发病风险之间的关系,以及脑脊液中淀粉样蛋白-β(Aβ)和p-Tau的水平。此外,一项独立的数据集也证实了上述结果。重要的是,本研究纳入了阿尔茨海默病免疫和微生物群倡议研究队列,以进一步验证血液中猫蛋白酶表达水平的变化,并研究其与认知水平和血浆中AD相关病理标记物的相关性。结果使用MR方法,我们观察到在训练和验证数据中,高水平的猫蛋白酶L(CTSL)与较低的AD风险相关。在观察队列中,我们发现与 Aβ- 认知功能未受损(CU)组相比,Aβ+ 认知功能受损(CI)组血液中 CTSL 表达水平降低。相关性分析显示,Aβ+ CI 组血液 CTSL 表达水平与迷你精神状态检查(MMSE)和蒙特利尔认知评估(MoCA)评分、血浆 Aβ42 和 Aβ42/40 水平呈负相关。中介分析表明,血浆Aβ42/40水平是Aβ+ CI参与者血液CTSL与MMSE评分之间关系的关键中介因素。
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Blood Cathepsins on the Risk of Alzheimer’s Disease and Related Pathological Biomarkers: Results from Observational Cohort and Mendelian Randomization Study

Background

Alzheimer’s disease (AD), the main type of dementia, involves in complex pathophysiological processes, including abnormal lysosomes function. Cathepsins are the predominant proteases responsible for the degradation of diverse substrates in the endo-lysosomal system. However, there was still a lack of systematic study on the causal association between cathepsins and AD.

Methods

This study utilized Mendelian randomization (MR) to investigate the association between blood cathepsins and the risk of AD, as well as the level of amyloid-β (Aβ) and p-Tau in cerebrospinal fluid. Furthermore, an independent dataset was employed to corroborate the above result. Importantly, this study incorporated the Alzheimer’s disease Immunization and Microbiota Initiative study Cohort to further validate the alteration of blood cathepsins expression level and examine its correlation with cognitive level and plasma AD-related pathological markers.

Results

Using MR method, we observed that high level of cathepsin L (CTSL) was associated with a lower risk of AD in both training and validation data. In observational cohort, we found there was decreased blood CTSL expression level in Aβ+ cognitive impaired (CI) group, compared with Aβ− cognitive unimpaired (CU) group. Correlation analysis revealed that blood CTSL expression level was negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) score, plasma Aβ42 and Aβ42/40 level in Aβ+ CI group. Mediation analysis showed that plasma Aβ42/40 level was the key mediator in the association between blood CTSL and MMSE score in Aβ+ CI participants.

Conclusion

This study revealed that blood CTSL was an important factor affecting the risk of AD, and it affected the cognitive level of AD patients through plasma Aβ42/40 level.

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来源期刊
The Journal of Prevention of Alzheimer's Disease
The Journal of Prevention of Alzheimer's Disease Medicine-Psychiatry and Mental Health
CiteScore
9.20
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0.00%
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0
期刊介绍: The JPAD Journal of Prevention of Alzheimer’Disease will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including: neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes.JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.We hope that JPAD with your contribution will play a role in the development of Alzheimer prevention.
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