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Exploring the relationship between ADAM9 and soluble ADAM10 in an Alzheimer's disease cellular model using induced pluripotent stem cells-derived cholinergic neurons

Grant number: 23/18020-0
Support Opportunities:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): July 31, 2024
Effective date (End): January 30, 2025
Field of knowledge:Health Sciences - Medicine - Psychiatry
Principal Investigator:Márcia Regina Cominetti
Grantee:Vanessa Alexandre da Silva
Supervisor: Erika Gyengesi
Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Research place: Western Sydney University, Campbelltown Campus, Australia  
Associated to the scholarship:23/00449-0 - Levels and activity of ADAM10, an Alzheimers disease serum biomarker, in different cellular compartments, BP.MS

Abstract

A disintegrin and metalloprotease 10 (ADAM10), a transmembrane protein, has been investigated as an Alzheimer's disease (AD) blood-based biomarker. Under physiological conditions, it is the major constitutive ±-secretase responsible for the non-amyloidogenic cleavage of amyloid precursor protein (APP), preventing the generation of the amyloid beta peptide (AB). In AD, however, there is a shift to the amyloidogenic pathway over the non-amyloidogenic, mediated mainly by the beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), which leads to increased levels of AB and its extracellular aggregation into amyloid plaques, one of the major pathological hallmarks of AD. The major results of our research group show that, compared to cognitively healthy subjects, persons living with AD have increased plasma levels of the proteolytically inactive soluble isoform of ADAM10 (sADAM10) and decreased platelet levels of active membrane-bound ADAM10 (mADAM10). Thus, the shift to the amyloidogenic pathway seen in AD might be due to increased levels of inactive sADAM10. This soluble isoform is generated via ectodomain shedding of mADAM10 mediated by ADAM9 and 15. Previous studies have shown that overexpression of ADAM9 increases the levels of sADAM10 in the medium and decreases membrane-bound mADAM10; the contrary is observed upon its inhibition. Thus, we hypothesize that, in AD, ADAM9 levels are altered, which leads to augmented ectodomain shedding of mADAM10, increasing the levels of extracellular sADAM10. To test this hypothesis, we want to investigate and correlate ADAM9, mADAM10, and sADAM10 levels in an AD cellular model based on induced pluripotent stem cells (iPSC)-derived cholinergic neurons.

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