Mass spectrometry-based proteomics empowers deep profiling of proteome and protein posttranslational modifications (PTMs) in Alzheimer’s disease (AD). Here we review the advances and limitations in historic and recent AD proteomic research. Complementary to genetic mapping, proteomic studies not only validate canonical amyloid and tau pathways, but also uncover novel components in broad protein networks, such as RNA splicing, development, immunity, membrane transport, lipid metabolism, synaptic function, and mitochondrial activity. Meta-analysis of seven deep datasets reveals 2,698 differentially expressed (DE) proteins in the landscape of AD brain proteome (n = 12,017 proteins/genes), covering 35 reported AD genes and risk loci. The DE proteins contain cellular markers enriched in neurons, microglia, astrocytes, oligodendrocytes, and epithelial cells, supporting the involvement of diverse cell types in AD pathology. We discuss the hypothesized protective or detrimental roles of selected DE proteins, emphasizing top proteins in “amyloidome” (all biomolecules in amyloid plaques) and disease progression. Comprehensive PTM analysis represents another layer of molecular events in AD. In particular, tau PTMs are correlated with disease stages and indicate the heterogeneity of individual AD patients. Moreover, the unprecedented proteomic coverage of biofluids, such as cerebrospinal fluid and serum, procures novel putative AD biomarkers through meta-analysis. Thus, proteomics-driven systems biology presents a new frontier to link genotype, proteotype, and phenotype, accelerating the development of improved AD models and treatment strategies.

中文翻译：

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阿尔茨海默病的蛋白质组学景观：对发病机制和生物标志物发现的新见解

基于质谱的蛋白质组学能够对阿尔茨海默病 (AD) 中的蛋白质组和蛋白质翻译后修饰 (PTM) 进行深入分析。在此，我们回顾历史和近期 AD 蛋白质组学研究的进展和局限性。作为遗传图谱的补充，蛋白质组学研究不仅验证了典型的淀粉样蛋白和 tau 通路，而且还揭示了广泛蛋白质网络中的新成分，例如 RNA 剪接、发育、免疫、膜运输、脂质代谢、突触功能和线粒体活性。对七个深度数据集的荟萃分析揭示了 AD 脑蛋白质组景观中的 2,698 个差异表达 (DE) 蛋白质（n = 12,017 个蛋白质/基因），涵盖 35 个报告的 AD 基因和风险位点。DE 蛋白含有富含神经元、小胶质细胞、星形胶质细胞、少突胶质细胞和上皮细胞的细胞标记物，支持多种细胞类型参与 AD 病理学。我们讨论了选定的 DE 蛋白的假设保护或有害作用，强调“淀粉样蛋白组”（淀粉样蛋白斑中的所有生物分子）和疾病进展中的顶级蛋白。全面的 PTM 分析代表了 AD 分子事件的另一层。特别是，tau PTM 与疾病阶段相关，并表明个体 AD 患者的异质性。此外，脑脊液和血清等生物体液的前所未有的蛋白质组学覆盖，通过荟萃分析获得了新的假定的 AD 生物标志物。因此，蛋白质组学驱动的系统生物学提供了连接基因型、蛋白质型和表型的新领域，加速了改进的 AD 模型和治疗策略的开发。