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

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.

Automated summary

Alzheimer's disease (AD) is a neurodegenerative disease associated with aging, which is more common in women than men. Hormone replacement therapy, particularly estrogen, has been shown to reduce memory loss in menopausal women by inducing autophagy to remove protein aggregates. This study found that 17β-estradiol induces autophagy by activating AMPK, independent of mTOR signals. Furthermore, it was discovered that 17β-estradiol increases LC3-II levels and clears tau protein through autophagy.