Modulation of ADAM10 by oxidized low-density lipoprotein (oxLDL) and advanced glycation end products (AGEs) in an in vitro blood-brain barrier model

• Grant number: 25/24455-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2027
• End date: December 31, 2029
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Márcia Regina Cominetti
• Grantee: Thaís Antonia Alves Fernandes
• 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

Abstract

The global population is undergoing a rapid aging The global population is undergoing a rapid aging process, contributing to an increased prevalence of chronic non-communicable diseases, such as neurodegenerative disorders - notably Alzheimer's disease (AD), diabetes mellitus, and cardiovascular diseases. These conditions are associated with elevated production of oxysterols (OxS) and advanced glycation end-products (AGEs), which interact with the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the receptor for advanced glycation end-products (RAGE), activating inflammatory and oxidative pathways that lead to neuronal death and blood-brain barrier (BBB) dysfunction. Environments rich in AGEs and OxS promote these mechanisms and foster the accumulation of B-amyloid (AB) peptide and hyperphosphorylated tau (p-tau) protein, both implicated in the pathophysiology of AD. A disintegrin and metalloproteinase 10 (ADAM10) plays a key role in regulating these processes, influencing the production of LOX-1, RAGE, intercellular adhesion molecule-1 (ICAM-1), vascular endothelial cadherin (VE-cadherin), and vascular endothelial growth factor (VEGF). However, there remains a scarcity of studies integrating these mechanisms in in vitro blood-brain barrier models. Therefore, this study aims to evaluate how excessive LDLox and AGEs modulate ADAM10 expression and how this regulation affects A¿ and p-tau levels. The results may help clarify mechanisms linking metabolism, inflammation, and neurodegeneration, enabling new diagnostic and therapeutic strategies in AD. (AU)