Evaluation of estrogenic compounds in mitochondrial dysfunction and cellular metabolism in a tauopathy cell model

• Grant number: 21/11960-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2021
• End date: October 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Rodrigo Portes Ureshino
• Grantee: Arthur Luiz Miranda Nicastro
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated research grant: 16/20796-2 - Study of estrogen receptors mediated autophagy against tau toxicity in cell and zebrafish models, AP.JP

Abstract

Tauopathies comprise a group of neurodegenerative diseases characterized by the presence of tau protein aggregates, in which Alzheimer's Disease is the most prevalent and occurs more frequently in women. In this context, recent studies have demonstrated the neuroprotective role of estrogens and their antioxidant effect in models of oxidative stress, however, the action of estrogen analogs and aromatase inhibitors in mitochondrial dysfunction that occurs in neurodegenerative diseases such as tauopathies has not been fully elucidated. Our group has screened a library of compounds that act on nuclear and membrane estrogen receptors, analyzing their potential to reduce the tau protein in a model of tauopathy, and 5 compounds were selected. Thus, this project aims to evaluate the action of these compounds and 17²-estradiol on mitochondrial bioenergetics in SH-SY5Y cells with overexpression of the tau 0N4R isoform (wild type or mutated P301L), by measuring two parameters: ATP and cAMP production. For this, measurements of ATP and cAMP production will be performed by fluorimetry methodology. Furthermore, the effects of estrogenic compounds on mitochondrial morphology will be observed by confocal microscopy. Thus, the evaluation of estrogenic compounds in mitochondrial dysfunction may provide important information to investigate a drug with potential use for neurodegenerative diseases, such as Alzheimer's disease. (AU)