Identification of molecular mechanisms associated with binding of soluble ²-amyloid peptide oligomers in adult human neural tissue slices

• Grant number: 22/12904-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2023
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Adriano Silva Sebollela
• Grantee: Giovanna Orlovski Nogueira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 24/10164-5 - High-resolution imaging of human brain slice cultures challenged with A² oligomers, BE.EP.DD

Abstract

Alzheimer's Disease (AD) is a proteinopathy responsible for most cases of dementia today. Its clinical manifestations are associated with neuronal damage and loss triggered by the binding of soluble ²-amyloid peptide oligomers (A²Os). The current project proposes using cultures of adult human brain tissue slices, prepared using tissue obtained from patients undergoing neurosurgical procedures, as a model for the study of molecular and cellular changes associated with binding and consequent neurotoxicity of A²Os, relevant to Alzheimer's Disease. The slices in culture will be challenged with A²Os to quantify their binding on the cell surface and eventual morphological changes, identification of binding sites, toxicity, deleterious effects on cellular metabolism and synaptic transmission (assessed by electrophysiology and neurotransmitter dosage), among others, and reversal of these effects using the scFv-like antibody NUsc1. Thus, this project aims to contribute to understanding pathological cellular changes caused by A²Os in an adult human CNS model, in addition to consolidating our ex vivo culture model as a preferred platform for studying neurodegenerative diseases typical of the adult human brain. (AU)