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蛋白质组学分析显示，血浆 EFEMP1 和 CXCL12 可作为神经退行性变的生物标志物和决定因素。

Proteomic analyses reveal plasma EFEMP1 and CXCL12 as biomarkers and determinants of neurodegeneration.

机构信息

Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

Artificial Intelligence in Biomedical Imaging Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

出版信息

Alzheimers Dement. 2024 Sep;20(9):6486-6505. doi: 10.1002/alz.14142. Epub 2024 Aug 11.

DOI:10.1002/alz.14142
PMID:39129354
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11497673/
Abstract

INTRODUCTION

Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes.

METHODS

We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n = 815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk.

RESULTS

Plasma proteins associated with distinct patterns of age- and AD-related atrophy were also associated with plasma/cerebrospinal fluid (CSF) AD biomarkers, cognition, AD risk, as well as mid-life (20-year) and late-life (8-year) dementia risk. EFEMP1 and CXCL12 showed the most consistent associations across cohorts and were mechanistically implicated as determinants of brain structure using genetic methods, including Mendelian randomization.

DISCUSSION

Our findings reveal plasma proteomic signatures of unique aging- and AD-related brain atrophy patterns and implicate EFEMP1 and CXCL12 as important molecular drivers of neurodegeneration.

HIGHLIGHTS

Plasma proteomic signatures are associated with unique patterns of brain atrophy. Brain atrophy-related proteins predict clinically relevant outcomes across cohorts. Genetic variation underlying plasma EFEMP1 and CXCL12 influences brain structure. EFEMP1 and CXCL12 may be important molecular drivers of neurodegeneration.

摘要

简介

对独特的脑萎缩模式的血浆蛋白质组分析可能阐明神经退行性变的外周驱动因素，并确定预测临床相关结果的新生物标志物。

方法

我们确定了与巴尔的摩纵向衰老研究（n=815）中机器学习衍生的与衰老和阿尔茨海默病（AD）相关的脑萎缩模式相关的蛋白质组学特征。使用来自五个队列的数据，我们检查了候选蛋白是否与 AD 内表型和长期痴呆风险相关。

结果

与特定的年龄和 AD 相关萎缩模式相关的血浆蛋白也与血浆/脑脊液（CSF）AD 生物标志物、认知、AD 风险以及中年（20 年）和晚年（8 年）痴呆风险相关。EFEMP1 和 CXCL12 在所有队列中表现出最一致的关联，并且通过遗传方法，包括孟德尔随机化，被认为是脑结构的决定因素。

讨论

我们的研究结果揭示了与独特的与衰老和 AD 相关的脑萎缩模式相关的血浆蛋白质组学特征，并表明 EFEMP1 和 CXCL12 是神经退行性变的重要分子驱动因素。

重点

血浆蛋白质组学特征与脑萎缩的独特模式相关。与脑萎缩相关的蛋白可预测各队列的临床相关结局。血浆 EFEMP1 和 CXCL12 下的遗传变异影响脑结构。EFEMP1 和 CXCL12 可能是神经退行性变的重要分子驱动因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/15308556bcf3/ALZ-20-6486-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/6f5cb3e016f4/ALZ-20-6486-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/e83b3435810f/ALZ-20-6486-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/e1851d14a107/ALZ-20-6486-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/f851baf193b4/ALZ-20-6486-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/a66966538c60/ALZ-20-6486-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/15308556bcf3/ALZ-20-6486-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/6f5cb3e016f4/ALZ-20-6486-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/e83b3435810f/ALZ-20-6486-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/e1851d14a107/ALZ-20-6486-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/f851baf193b4/ALZ-20-6486-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/a66966538c60/ALZ-20-6486-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7815/11497673/15308556bcf3/ALZ-20-6486-g002.jpg

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