Evaluation of neuroinflammation, dynamic of synapses and interaction between organelles in cell model of Alzheimer's Disease

• Grant number: 22/12697-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2023
• End date: September 30, 2027
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Merari de Fátima Ramires Ferrari
• Grantee: Luísa Machado Pinheiro
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 24/22615-1 - Evaluation of neuroinflammation and therapeutic approaches in iPSC derived neuron and microglia co-culture containing PSEN1 Alzheimer's mutation, BE.EP.DD

Abstract

Alzheimer's disease (AD) is considered the most harmful form of dementia in the elderly population and according to the 2021 Alzheimer's Disease International report, there are currently 55 million people in the world living with dementia, and that number tends to grow to about 139 million by 2050 as the population ages. Nevertheless, at present, there are no effective treatments, and this is likely due to the incomplete understanding of the pathophysiology.One of the most widely accepted hypothesis designed to explain AD pathogenesis is the amyloid cascade, which invokes the accumulation of extracellular plaques and intracellular tangles as playing a fundamental role in the course and progression of the disease. However, other biochemical and morphological features are also present in AD, manifesting itself at earlier moments of disease development such as altered mitochondrial dynamics and calcium metabolism, factors associated with increased contact sites between endoplasmic reticulum and mitochondria (MAM). Thus, this study aims to evaluate the hypothesis of MAM as a starting point for the development of AD, through tests that evaluate interactions between organelles, intracellular dynamics of Ca2+ as well as its relationship with the dynamics of synapses, in addition to that we will also evaluate the progress of the disease through the visualization of neuroinflammatory patterns.To do so, we will use neurons derived from skin-induced pluripotency cells of Alzheimer's patients with mutation in the presenilin-2 gene, which is responsible for many cases of early onset of the disease and associated with an increase in the number of contact sites between RE-mitochondria.Thus, we aim to identify new possible markers allowing early diagnosis of AD as well as therapeutic targets for future studies. (AU)