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

Autor: Costa AJ; Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil., Oliveira RB; Universidade Federal de São Paulo, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Department of Biological Sciences, Diadema, SP, Brazil; Universidade Federal de São Paulo, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, São Paulo, SP, Brazil., Wachilewski P; Universidade Federal de São Paulo, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Department of Biological Sciences, Diadema, SP, Brazil; Universidade Federal de São Paulo, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, São Paulo, SP, Brazil., Nishino MS; Universidade Federal de São Paulo, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Department of Biological Sciences, Diadema, SP, Brazil; Universidade Federal de São Paulo, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, São Paulo, SP, Brazil., Bassani TB; Universidade Federal de São Paulo, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Department of Biological Sciences, Diadema, SP, Brazil; Universidade Federal de São Paulo, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, São Paulo, SP, Brazil., Stilhano RS; Department of Physiological Sciences, Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brazil., Cerutti JM; Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Morphology and Genetics, São Paulo, SP, Brazil., Nozima B; Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Morphology and Genetics, São Paulo, SP, Brazil., Porto CS; Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil., Pereira GJDS; Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil., Ramirez AL; Cambridge Institute for Medical Research, Cambridge, United Kingdom., Smaili SS; Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil., Ureshino RP; Universidade Federal de São Paulo, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Department of Biological Sciences, Diadema, SP, Brazil; Universidade Federal de São Paulo, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, São Paulo, SP, Brazil. Electronic address: rpureshino@gmail.com.
Jazyk: angličtina
Zdroj: Brain research [Brain Res] 2022 Nov 15; Vol. 1795, pp. 148079. Date of Electronic Publication: 2022 Sep 08.
DOI: 10.1016/j.brainres.2022.148079
Abstrakt: 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 17β-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 17β-estradiol induces autophagy by activating AMPK in a concentration-dependent manner, independent of mTOR signals. The estrogen receptor α (ERα) agonist, PPT, also induced autophagy, while the ERα antagonist, MPP, substantially attenuated the 17β-estradiol-mediated autophagy induction. Notably, 17β-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 ERα involvement in non-genomic estrogenic pathway activation. Furthermore, 17β-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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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