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Levels and activity of ADAM10, an Alzheimers disease serum biomarker, in different cellular compartments

Grant number: 23/00449-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): May 01, 2023
Effective date (End): February 28, 2025
Field of knowledge:Health Sciences - Medicine - Psychiatry
Principal Investigator:Márcia Regina Cominetti
Grantee:Vanessa Alexandre da Silva
Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Associated research grant:21/01863-9 - Biology and function of ADAM10 isoforms for differential diagnosis of Alzheimer's Disease by electrochemical sensors, AP.TEM
Associated scholarship(s):23/18020-0 - Exploring the relationship between ADAM9 and soluble ADAM10 in an Alzheimer's disease cellular model using induced pluripotent stem cells-derived cholinergic neurons, BE.EP.MS

Abstract

With the increase in life expectancy, cases of neurodegenerative diseases such as Alzheimer's disease (AD), have also risen. Characterized by a progressive neurodegeneration and cognitive impairment, AD has a major pathological hallmark: the hyperphosphorylated tau protein, which aggregates intracellularly into neurofibrillary tangles, and the beta-amyloid peptide (A²), which forms senile plaques extracellularly. Newer drugs released in 2021 and 2023, i.e., monoclonal antibodies for A², have dramatically changed the pharmacological treatment of the disease. In this context, biomarkers are important tools for AD early detection, diagnosis, and evaluation of the effects of drug treatments on AD since the early stages of the disease are a valuable therapeutic window. Nowadays, the major biomarkers employed in clinical settings are magnetic resonance imaging and A² and tau levels measurement in the cerebrospinal fluid. However, those options present some disadvantages, mainly related to the invasive method, i.e., lumbar punction and the high costs of imaging analyses. In this context, biomarkers obtained from other tissues, such as blood, are preferable. ADAM10, the major ±-secretase responsible for amyloid protein precursor (APP) cleavage in the non-amyloidal pathway, has shown great potential as an AD serum biomarker. Although widely investigated, many questions regarding its activity, such as its activity state in different cellular fractions, remain. Thus, the objective of our study is to evaluate the levels and activity of ADAM10 in different cellular compartments to establish a relation between the protein location and activity. For that, neuroblastoma SH-SY5Y cells will be differentiated into neuron-like cells and fractioned into the membrane, cytosol, and organelles fractions, and ADAM10 levels and activity will be measured through western blotting and enzymatic activity assays in each fraction.

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