Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery

• Published in: Molecular neurodegeneration Vol. 16; no. 1; pp. 55 - 16
• Main Authors: Bai, Bing, Vanderwall, David, Li, Yuxin, Wang, Xusheng, Poudel, Suresh, Wang, Hong, Dey, Kaushik Kumar, Chen, Ping-Chung, Yang, Ka, Peng, Junmin
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12.08.2021; BioMed Central; BMC
• Subjects: Advertising executives; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amino acids; Analysis; Astrocytes; Asymptomatic Diseases; Biomarker; Biomarkers; Blood Proteins - analysis; Cerebrospinal fluid; Cerebrospinal Fluid Proteins - analysis; Chromatography, Liquid; Cognitive Dysfunction - metabolism; Data Mining; Databases, Protein; Datasets as Topic; Dementia; Development and progression; Epithelial cells; Gene mapping; Genes; Genomics; Genotypes; Humans; Hypotheses; Ions; Labeling; Lipid metabolism; Mass spectrometry; Mass spectroscopy; Meta-analysis; Meta-Analysis as Topic; Microglia; Mitochondria; Mutation; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurodegenerative diseases; Oligodendrocytes; Pathogenesis; Peptides; Phenotypes; Plaque, Amyloid - chemistry; Protein Processing, Post-Translational; Proteins; Proteome; Proteomes; Proteomics; Proteomics - methods; PTM; Review; Scientific imaging; Senile plaques; Tandem Mass Spectrometry; Tau protein; United States > US; Biomarker; Abeta; Alzheimer’s disease; Amyloidome; Pathogenesis; Proteomics; PTM; Proteome; Tau; Mass spectrometry
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-021-00474-z

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.