Many studies have shown the effects of estrogens in neuroprotection in neurodegenerative processes, such as in Alzheimer's Disease. Furthermore, modulation of autophagy is one of the promising strategies for the treatment of dementias associated with the formation of protein aggregates, which occur in Tauopathies, where the main component is the tau protein. However, the role of estrogens in regulating autophagy has to be elucidated in the central nervous system. Thus, this project aims to investigate the involvement of estrogen receptors ER-alpha, ER-beta and GPER in the modulation of autophagy pathways, focusing on cellular protection in cell and animal models of neurodegenerative disease. In the first part of the project it will be established and characterized a cellular model of neurons overexpressing human tau protein. The autophagy induction mediated by activation/inhibition will be evaluated, searching for compounds that are able to reduce the protein accumulation. In parallel, it will be studied the intracellular signaling and bioenergetics modulated by activation/inhibition of estrogen receptors, by using pharmacological approaches, as well as knockout of estrogen receptors. In the second part of the project it will be used a Zebrafish model to study the role of estrogen receptors in the induction of autophagy in vivo, and subsequently the possible neuroprotective role against the human tau protein. Thus, considering that the regulation of estrogen receptor plays an important role in cytoprotection, its interrelation with the autophagy process can open new possibilities of combination therapy for dementia, as occurs in Alzheimer's Disease. (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
URESHINO, RODRIGO PORTES;
ERUSTES, ADOLFO GARCIA;
BASSANI, TAYSA BERVIAN;
GUARACHE, GABRIEL CICOLIN;
NASCIMENTO, ANA CAROLINA;
COSTA, ANGELICA JARDIM;
SMAILI, SORAYA SOUBHI;
DA SILVA PEREIRA, GUSTAVO JOSE.
The Interplay between Ca2+ Signaling Pathways and Neurodegeneration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,
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