Study of the estrogen-modulated autophagy in a neurodegeneration model by tau protein superexpression in zebrafish

• Grant number: 19/11546-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2019
• End date: July 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Rodrigo Portes Ureshino
• Grantee: Giulia Ventura Portella
• 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

Alzheimer's disease is clinically characterized by a decrease of cognitive functions and dementia. The main risk factor for this disease is the aging process, and its incidence is higher in women. Many studies have pointed out that estrogens play a role in neuroprotection and neurodegenerative processes. However, the intracellular mechanisms and pathways activated by these hormones still need to be further explored. It is well known that the formation of neurofibrillary tangles, mainly formed by hyperphosphorylated tau protein, contributes to the pathogenesis of this disease, and it is related to dementia. Therefore, therapeutic strategies that aims to remove these protein aggregates are desirable, for example, by the modulation of autophagy. This project aims to investigate the role of estrogen receptors in intracellular signaling pathways in in vivo model of tauopathies. Thus, we will establish a zebrafish model of tauopathies by microinjection of plasmids containing the sequence of tau protein, and degeneration will be evaluated in the larval stage. Zebrafish embryos will be submitted to treatments with agonists and antagonists of estrogen receptors, as well as receptor knockdown (by injection of morpholino oligomers), aiming to validate the data obtained with experiments in a cellular model of tauopathy. In addition, in vivo intracellular signaling assays will be performed, such as Ca2+ signaling experiments, evaluation of mitochondrial membrane potential and generation of reactive oxygen species. Measurements of ATP and evaluation of mitochondrial respiratory function by the activation of estrogen receptors will be carried out, as well as the estrogen signaling pathway (genomic and non-genomic actions) and the expression of the genes identified as targets of the autophagic pathway mediated by estrogen. Therefore, the evaluation of estrogen receptors-related signaling in cytoprotection in an in vivo model is relevant to delineate new pharmacological therapies for dementias, such as in Alzheimer's disease. (AU)