Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.
Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.
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血清蛋白质组学揭示了阿尔茨海默病中 APOE 依赖和独立的蛋白质特征。
DOI：
10.1101/2023.11.08.23298251
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Gud
中科院分区：
文献类型：
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作者：
Frick,ElisabetA;Emilsson,Valur;Jonmundsson,Thorarinn;Steindorsdottir,AnnaE;Johnson,ErikCB;Puerta,Raquel;Dammer,EricB;Shantaraman,Anantharaman;Cano,Amanda;Boada,Mercè;Valero,Sergi;García-González,Pablo;Gudmundsson,EliasF;Gud
目前对迟发性阿尔茨海默病（LOAD）的早期干预，预防和治疗的需求需要更深入地了解潜在的分子过程，这可能有助于生物标志物和药物靶点的发现。利用高通量蛋白质组学测量的血清从一个前瞻性的人口为基础的队列的老年人（n= 5，294），我们确定了303个独特的蛋白质与事件负载（中位随访12.8年）。超过40%的这些蛋白质与LOAD相关，与APOE-ε4携带者状态无关。这些蛋白质参与神经元过程，并与脑和脑脊液中LOAD的蛋白质特征重叠。我们发现17个蛋白质的负载相关性强烈依赖于载脂蛋白E-ε4载体状态。他们中的大多数人表现出与脑脊液中LOAD的一致关联，三分之一具有脑特异性基因表达。值得注意的是，在双向孟德尔随机化分析中确定，该组中的四种蛋白（TBCA、ARL 2、S100 A13和IRF 6）被APOE-ε4下调，但由于LOAD而上调，反映了对疾病发作的潜在反应。因此，这些蛋白质与LOAD的直接关联在APOE-ε4基因型调整后逆转，我们在外部队列（n=719）中重复了这一发现。我们的研究结果提供了对可能导致LOAD发展和早期检测的失调途径的深入了解，包括独立和依赖于APOE-ε4的途径。重要的是，我们在循环中发现的许多LOAD相关蛋白在脑组织中表达，并与AD有直接联系。因此，本文鉴定的蛋白质及其上游调节途径为LOAD提供了循环生物标志物和治疗靶点候选物的新来源。
The current demand for early intervention, prevention, and treatment of late onset Alzheimer’s disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n=5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE-ε4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE-ε4 genotype adjustment, a finding which we replicate in an external cohort (n=719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE-ε4. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.