Dysregulation of Neuropeptides and Proteases in Human Alzheimer’s Disease and Potential Therapeutic Strategy

Neuropeptides serve as important neurotransmitters in the nervous system, essential for cell-cell communication among neurons performing diverse functions. This thesis aims to summarize, analyze, and provide further insight into the results of the Podvin et al. (2022) study, which applied methods from the Jiang et al. (2021) paper, and the implications that the results may have in the field for identifying therapeutic targets. The Jiang et al. (2021) study identified unique neuropeptides generated from differing proteases in dense core secretory vesicles (DCSVs) at a pH of 5.5 compared to the extracellular pH of 7.2. The production of distinct neuropeptides in purified secretory vesicles isolated from the bovine adrenal medulla (also known as chromaffin granules) involved aspartic, cysteine, serine, and metallo proteases. Through the use of neuropeptidomics, proteomics, and substrate profiling, the study by Podvin et al. (2022) demonstrated significantly dysregulated neuropeptides, proteins, proteases, and flanking residues of neuropeptides with proneuropeptide precursors between AD and aged-matched control synaptosomes. Additionally, through an extensive review conducted on the results of the Podvin et al. (2022) study on the proneuropeptides and proteases found to be dysregulated between AD and age-matched control, they were explored for their roles in either protection from AD pathology or as causative agents. The results from these studies indicate that combining proteomics, neuropeptidomics, and substrate profiling may be of great importance in exploring different disease pathogenesis to understand the dysregulation occurring in AD and for exploring new targets for drug therapies