Evaluation of treatment with estrogenic compounds on mitochondrial function in an in vitro model of tauopathies

• Grant number: 24/11078-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Rodrigo Portes Ureshino
• Grantee: Haline Honório Bannitz Guimarães
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Tauopathies are neurodegenerative diseases characterized by decreased cognitive function, dementia, and in some cases there are changes in mobility. Alzheimer's disease presents both the amyloid component (²-amyloid aggregates) and the tauopathy, characterized by the atypical hyperphosphorylation of the tau protein, a cellular component that stabilizes microtubules, which in a pathological condition can be found as tangles in pairs of helical filaments. In this conformation, tau protein leads to a cellular neurotoxic state with compromised axonal transport of organelles, such as mitochondria. This organelle participates in several neuronal functions, such as cellular bioenergetics, calcium homeostasis, apoptosis and also steroidogenesis. Many studies indicate that estrogens, mainly 17²-estradiol, and estrogen receptors have neuroprotective functions and mitochondrial regulation. Thus, this project aims to investigate the roles of three estrogenic compounds (bazedoxifene, anastrozole and estropipate) and estradiol in mitochondrial function in a cellular model of tauopathies and in isolated mitochondria from this model. Oxygraphy methodologies, evaluation of membrane potential by fluorescence, production of reactive oxygen species (ROS), mitochondrial isolation and treatment with estrogenic compounds will be used to analyze the mechanisms, in cellular models of SH-SY5Y cells with conditional overexpression (Tet-On system) of tau protein. This study seeks to contribute to the understanding of the relationship between tau protein and mitochondrial function, focusing on the role of estrogenic compounds in a cellular model of AD and other dementias.