Proteomic study of Alzheimer’s Disease

Madhavi Bhatia, National Pharmaceutical Education and Research, Guwahati

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is also age-associated. Approximately 5.8 million people are affected by this disease in the United States. Typically the onset of AD mostly occurs after the age of 65. The primary clinical manifestations of the disease cover profound cognitive decline, progressive memory loss, retrograde, and anterograde amnesia. These are accompanied by histopathological changes like degeneration of the hippocampus and subsequent loss of cortical matter. The disease is accompanied by amyloid plaques which are comprised of amyloid-β (Aβ) peptides, and neurofibrillary tangles (NFT) that contain hyperphosphorylated tau which is used to characterize the various stages of the disease(Braak stages). AD also manifests movements and psychological disorders as well as sleep disturbances. 

AD pathogenesis:

The fundamental information regarding Alzheimer’s disease pathogenesis comes from complementary genetic/genomic and biochemical/ proteomic studies. After integrating biochemical and genetic evidence, it was found that sequential proteolytic cleavage of β-amyloid precursor (APP) by β-secretase (BACE1) and gamma-secretase (that contains (PSEN1/PSEN2) produces amyloidogenic  Aβ peptides. Thus, Aβ species from APP cleavage acts as a central role in driving AD pathogenesis. Hyperphosphorylated tau is a dominant component of neurofibrillary tangles in AD brain tissues. Mutations to the tau gene (MAPT) might be linked to several other neurodegenerative diseases, such as frontotemporal dementia. Misfolded Aβ and tau may act as pathological seeds during neurodegeneration. The Multi-omics approach offers a requisite as well as a systematic tool for knowing the complexity of the AD. 

Proteomics technology:

Proteomics technologies are used to explore underlying biomolecular mechanisms of the disease in different time periods. In the pre-genomic era, MS analysis is done to know the Alzheimer’s disease proteins (Aβ and tau). LC-ESI-MS and MALDI-TOF-MS are used for the investigation of the composition of amyloid plaques, identifying the different Aβ peptides in soluble and insoluble forms. MS also helps in the identification of abnormally modified tau species, includes phosphorylation, deamidation, and acetylation. Laser capture microdissection (LCM) is a technique used for dissecting and isolating a tissue region of interest. The technique helps in the characterization of amyloid plaque, the plaques are labelled with thioflavin-S were captured which was followed by protein extraction and MS analysis. After doing LC-MS, the most enriched proteins were Aβ, tau, APOE, and complement components were obtained. In AD, synaptic loss occurs early and is highly corrected with the help of cognitive impairment. That is exactly why the synapse subproteome has been done. Subproteome studies helped to characterize the whole proteomic changes. It also helped to identify protein modules that were enriched in neurons, microglia, and astrocytes. Interactome and pathway analysis of the DE proteins showed 17 altered pathways, that included Aβ, WNT, TGF-β/BMP, G protein, etc. The deep AD proteomics results indicated a broad, dynamic protein perturbation during AD progression.

Conclusion:

 It is critical to understand that there is a gap between the generation of proteomics data and the discovery of disease drivers or biomarkers. Because proteome profiling reveals only disease-correlated components, but correlation does not necessarily comply with the causation of the disease. After the recent identification of a large number of DE proteins in AD, the next is the identification and validation of the underlying mechanisms that contribute to the molecular changes. Novel AD models are developed following the hypothesis from the molecular insights and thus provide potential therapeutic strategies and biomarkers for AD and subtypes of AD.

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Reference: Bai, B., Vanderwall, D., Li, Y., Wang, X., Poudel, S., Wang, H., Dey, K. K., Chen, P.-C., Yang, K., & Peng, J. (2021). Proteomic landscape of Alzheimer’s Disease: Novel insights into pathogenesis and biomarker discovery. Molecular Neurodegeneration, 16(1), 55. https://doi.org/10.1186/s13024-021-00474-z

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About the author: Madhavi Bhatia is currently pursuing a Master of Science in Pharmaceutical Biotechnology from NIPER, Guwahati. Her area of interest lies in understanding the role of gene mutation in the development of various diseases and developing a treatment for such diseases.