Membrane estrogen receptor ERa activation improves tau clearance via autophagy induction in a tauopathy cell model

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Costa, Angelica Jardim ; Oliveira, Rafaela Brito ; Wachilewski, Patricia ; Nishino, Michelle Sayuri ; Bassani, Taysa Bervian ; Stilhano, Roberta Sessa ; Cerutti, Janete Maria ; Nozima, Bruno ; Porto, Catarina Segreti ; da Silva Pereira, Gustavo Jose ; Ramirez, Ana Lopez ; Smaili, Soraya Soubhi ; Ureshino, Rodrigo Portes

• Document type: Journal article
• Source: Brain Research; v. 1795, p. 16-pg., 2022-09-13.

Abstract

Alzheimer's disease (AD) is the most prevalent aging-associated neurodegenerative disease, with a higher incidence in women than men. There is evidence that sex hormone replacement therapy, particularly estrogen, reduces memory loss in menopausal women. Neurofibrillary tangles are associated with tau protein aggregation, a characteristic of AD and other tauopathies. In this sense, autophagy is a promising cellular process to remove these protein aggregates. This study evaluated the autophagy mechanisms involved in neuroprotection induced by 17 ss-estradiol (E2) in a Tet-On inducible expression tauopathy cell model (EGFP-tau WT or with the P301L mutation, 0N4R isoform). The results indicated that 17 ss-estradiol induces autophagy by activating AMPK in a concentration-dependent manner, independent of mTOR signals. The estrogen receptor a (ERa) agonist, PPT, also induced autophagy, while the ERa antagonist, MPP, substantially attenuated the 17 ss-estradiol-mediated autophagy induction. Notably, 17 ss-estradiol increased LC3-II levels and phosphorylated and total tau protein clearance in the EGFP-tau WT cell line but not in EGPF-tau P301L. Similar results were observed with E2-BSA, a plasma membrane-impermeable estrogen, suggesting membrane ERa involvement in non-genomic estrogenic pathway activation. Furthermore, 17 ss-estradiol-induced autophagy led to EGFP-tau protein clearance. These results demonstrate that modulating autophagy via the estrogenic pathway may represent a new therapeutic target for treating AD. (AU)

• FAPESP's process: 19/02821-8 - Autophagy modulation by cannabinoids: neuroprotection in Parkinson's Disease
• Grantee: Soraya Soubhi Smaili
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/04709-8 - Evaluation of potential therapeutically compounds for SARS-CoV-2: focus on estrogen-related compounds, autophagy modulators and ACE2
• Grantee: Rodrigo Portes Ureshino
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/14722-4 - Two-Pore Channels receptors and TFEB-3 autophagy modulation in human hepatocellular carcinoma
• Grantee: Gustavo José da Silva Pereira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/20796-2 - Study of estrogen receptors mediated autophagy against tau toxicity in cell and zebrafish models
• Grantee: Rodrigo Portes Ureshino
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 17/23616-8 - Analysis of progestagen receptors-mediated autophagy against tau toxicity in cell model of tauopathy
• Grantee: Taysa Bervian Bassani
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/10863-7 - Study of lipophagy mediated by two-pore channels receptors
• Grantee: Gustavo José da Silva Pereira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/16719-8 - The role of estrogen receptors in autophagy in cellular model of Tauopathy
• Grantee: Michelle Sayuri Nishino
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 18/02762-9 - Evaluation of estrogen-mediated neuroprotection in cellular model of the tauopathy
• Grantee: Rafaela Brito Oliveira
• Support Opportunities: Scholarships in Brazil - Master