Mapping Post-Translational Modifications in Brain Regions in Alzheimer's Disease Using Proteomics Data Mining.

ABSTRACT

Alzheimer's disease (AD) is a leading cause of dementia and a neurodegenerative disease. Proteomics and post-translational modification (PTM) analyses offer new opportunities for a comprehensive understanding of pathophysiology of brain in AD. We report here multiple PTMs in patients with AD, harnessing publicly available proteomics data from nine brain regions and at three different Braak stages of disease progression. Specifically, we identified 7190 peptides with PTMs, corresponding to 2545 proteins from brain regions with intermediate tangles, and 6864 peptides with PTMs corresponding to 2465 proteins from brain regions with severe tangles. A total of 103 proteins with PTMs were expressed uniquely to intermediate tangles and severe tangles compared to no tangles. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis suggested the association of these proteins in AD progression through platelet activation. These modified proteins were also found to be enriched for the tricarboxylic acid (TCA) cycle, respiratory electron cycle, and detoxification of reactive oxygen species. The multi-PTM data reported here contribute to our understanding of the neurobiology of AD and highlight the prospects of omics systems science research in neurodegenerative diseases. The present study provides a region-wise classification for the proteins with PTMs along with their differential expression patterns, providing insights into the localization of these proteins upon modification. The catalog of multi-PTMs identified in the context of AD from different brain regions provides a unique platform for generating newer hypotheses in understanding the putative role of specific PTMs in AD pathogenesis.