Investigation of mitochondria alterations in in vivo and in vitro models of tauopathies: evaluation of estrogenic compounds treatment

• Grant number: 24/04261-8
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2024
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Rodrigo Portes Ureshino
• Grantee: Rodrigo Portes Ureshino
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Carla Máximo Prado ; Dr Louise Newson ; Roberta Sessa Stilhano Yamaguchi
• Associated scholarship(s): 25/05035-4 - Evaluation of epigenetic alterations of estrogen receptors in in vitro models of tauopathies, BP.IC; 25/00780-3 - Husbandry, handling and maintenance of tauopathy zebrafish model in a rack system, BP.TT

Abstract

The differential prevalence between genders is notable in neurodegenerative diseases, such as Alzheimer's disease (AD), and studies suggest that sex hormones play an important role in its pathophysiology. In AD and in other dementias, for example, intracellular inclusions of tau protein may be related to changes in processes such as autophagy and cellular metabolism. We have previously shown that 17²-estradiol plays a role in promoting tau protein reduction in a cellular model of tauopathy. Literature data indicate that there are changes in mitochondrial bioenergetics in tauopathies, and the investigation of potential neuroprotective agents that can modulate this interaction must be deeply investigated in cellular and animal models. In this context, zebrafish is a versatile animal model that can be used for neurodegenerative diseases investigations, as it produces a great number of embryos in a short period, in addition to the advantage of observing real-time microscopic phenomena. The main aims of this project are the analysis of mitochondrial changes in in vivo and in vitro models of tauopathies, and to evaluate the possible neuromodulatory effects of estrogenic compounds, considering the expression of genes and proteins related to signaling pathways, mitochondrial energy status and their function. For this we will use: 1) SH-SY5Y cells that conditionally overexpress the WT and P301L tau protein; 2) zebrafish model that overexpresses the tau protein. Real-time microscopy analysis and evaluation of mitochondrial bioenergetics will be performed, as well as treatments with estrogenic compounds previously selected form a compound library screening (FAPESP 2016/20796-2) to observe the effects on mitochondrial pathways. Thus, this project seeks to contribute to with knowledge and tools to study the potential consequences of tauopathies in the main cellular energy source, in addition to elucidating a possible relevant role of estrogenic compounds in AD and other dementias. (AU)