Abstract
The two estrogen receptors (ERs), ERα and ERβ, mediate the diverse biological functions of estradiol. Opposite effects of ERα and ERβ have been found in estrogen-induced cancer cell proliferation and differentiation as well as in memory-related tasks. However, whether these opposite effects are implicated in the pathogenesis of Alzheimer’s disease (AD) remains unclear. Here, we find that ERα and ERβ play contrasting roles in regulating tau phosphorylation, which is a pathological hallmark of AD. ERα increases the expression of miR-218 to suppress the protein levels of its specific target, protein tyrosine phosphatase α (PTPα). The downregulation of PTPα results in the abnormal tyrosine hyperphosphorylation of glycogen synthase kinase-3β (resulting in activation) and protein phosphatase 2A (resulting in inactivation), the major tau kinase and phosphatase. Suppressing the increased expression of miR-218 inhibits the ERα-induced tau hyperphosphorylation as well as the PTPα decline. In contrast, ERβ inhibits tau phosphorylation by limiting miR-218 levels and restoring the miR-218 levels antagonized the attenuation of tau phosphorylation by ERβ. These data reveal for the first time opposing roles for ERα and ERβ in AD pathogenesis and suggest potential therapeutic targets for AD.
Highlights
Alzheimer’s disease (AD), the most common form of dementia, was first reported in 1906 by Alois Alzheimer
ERa was positively correlated with AT8, and ERb was positively correlated with Tau1 (Fig. 1C,D)
Given that there were no significant changes in ERa in aged wild-type mice, we only examined the correlation of tau phosphorylation with ERb and did not observe similar positive correlation of ERb with Tau1 (Fig. S1d)
Summary
Alzheimer’s disease (AD), the most common form of dementia, was first reported in 1906 by Alois Alzheimer. Hyperphosphorylated tau, which forms paired helical filaments, is the major component of NFTs (Johnson & Jenkins, 1999). The precise role of tau phosphorylation in the toxicity remains unclear, the abnormalities caused by hyperphosphorylated tau have been well studied. Abnormal tau hyperphosphorylation converts normal tau from a microtubule assembly-promoting to a microtubuledisrupting protein (Alonso et al, 1994). In AD brains, tau is hyperphosphorylated about three times more than that in normal brains, and it promotes misfolding of normal tau and coaggregates with it into filaments (Alonso et al, 1996). The levels of tau phosphorylation are positively correlated with cognitive deficits in multiple animal models and patients with AD (Mitchell et al, 2002; Zhu et al, 2004; Stancu et al, 2014). The development of tau-based therapeutic drugs for AD-related tauopathies will require the elucidation of the underlying mechanisms of how the abnormal phosphorylation is regulated
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