Neal Reem, Yang Zhiyi, Obideen Malik, Peterson Melissa, Shah Amil, Hajjar Ihab
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390.
Family Medicine and Osteopathic Manipulative Medicine, Texas College of Osteopathic Medicine, The University of North Texas Health Science Center.
Res Sq. 2025 Jan 16:rs.3.rs-5404760. doi: 10.21203/rs.3.rs-5404760/v1.
Although Amyloid-beta and Tau are the hallmarks of Alzheimer's Disease (AD), other protein pathways such as endothelial dysfunction may be involved and may precede cognitive symptoms. Our objective was to characterize the cerebrospinal fluid (CSF) proteomic profiles focusing on cardiometabolic-related protein pathways in individuals on the AD spectrum.
We performed CSF and plasma-targeted proteomics (276 proteins) from 354 participants of the Brain Stress Hypertension and Aging Program (BSHARP), of which 8% had preclinical AD, and 24% had MCI due to AD. We instituted a bioinformatic pipeline to generate data-driven protein modules, used "Hub" and "Critical" proteins within each module to describe protein signatures for each AD stage and then assessed their associations with clinical and biological AD traits. Finally, we completed pathway enrichment analysis to get insight into pathways that might be implicated in AD pathogenesis.
The 276 measured proteins clustered into five modules that were associated with CSF Amyloid-β42, Tau, and pTau. (all -value <0.05). A CSF protein AD signature was characterized by elevated levels of CSF Hepatocyte Growth Factor (), Intercellular and Vascular Cell Adhesion Molecule 1 (ICAM-1, ), Neuropilin 1 and 2 (, ), Scavenger Receptor Class B Member 2(), Plasminogen Activator, Urokinase (). We also found a significant difference in the CSF/Plasma ratio for the proteins associated with Cognitive Status and the Tau/Aβ42 ratio (TAR) in the CSF. Pathway enrichment analysis revealed that cell adhesion and endothelial dysfunction (all -value <0.05) were key mechanisms involved in AD pathogenesis, especially in the preclinical stage.
Our results suggest a proteomic signature in the CSF of individuals with preclinical AD that is driven by adhesion molecules and might be implicated in the pathogenesis of AD. Future studies investigating these pathways may provide insights into novel AD biomarkers and therapeutic targets.
尽管β淀粉样蛋白和 Tau 蛋白是阿尔茨海默病（AD）的标志，但其他蛋白质途径，如内皮功能障碍，可能也参与其中，并且可能早于认知症状出现。我们的目标是在处于 AD 谱系的个体中，以关注心脏代谢相关蛋白质途径为重点，对脑脊液（CSF）蛋白质组学特征进行表征。
我们对来自脑应激高血压与衰老项目（BSHARP）的 354 名参与者进行了脑脊液和血浆靶向蛋白质组学分析（检测 276 种蛋白质），其中 8%患有临床前 AD，24%因 AD 患有轻度认知障碍（MCI）。我们建立了一个生物信息学流程来生成数据驱动的蛋白质模块，使用每个模块内的“枢纽”和“关键”蛋白质来描述每个 AD 阶段的蛋白质特征，然后评估它们与临床和生物学 AD 特征的关联。最后，我们完成了通路富集分析，以深入了解可能与 AD 发病机制相关的通路。
所检测的 276 种蛋白质聚集成五个模块，这些模块与脑脊液淀粉样β蛋白 42、Tau 蛋白和磷酸化 Tau 蛋白相关（所有 p 值<0.05）。脑脊液蛋白质 AD 特征表现为脑脊液中肝细胞生长因子、细胞间黏附分子 1 和血管细胞黏附分子 1（ICAM - 1）、神经纤毛蛋白 1 和 2、清道夫受体 B 类成员 2、尿激酶型纤溶酶原激活剂水平升高。我们还发现，与认知状态相关的蛋白质的脑脊液/血浆比值以及脑脊液中的 Tau/淀粉样β蛋白 42 比值（TAR）存在显著差异。通路富集分析表明，细胞黏附及内皮功能障碍（所有 p 值<0.05）是 AD 发病机制中的关键机制，尤其是在临床前阶段。
我们的结果表明，临床前 AD 个体的脑脊液中存在一种由黏附分子驱动的蛋白质组学特征，这可能与 AD 的发病机制有关。未来对这些通路的研究可能会为新型 AD 生物标志物和治疗靶点提供见解。
