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Aging Cell. 2015 Oct;14(5):867-77. doi: 10.1111/acel.12366. Epub 2015 Jun 26.

Opposite effects of two estrogen receptors on tau phosphorylation through disparate effects on the miR-218/PTPA pathway.

Xiong YS1,2, Liu FF1,2, Liu D2,3,4, Huang HZ1,2, Wei N1,2, Tan L1,2, Chen JG2,5, Man HY6, Gong CX7, Lu Y2, Wang JZ1,2, Zhu LQ1,2,4.

Author information

1
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Disorder of Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
2
The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
3
Department of Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
4
Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
5
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
6
Department of Biology, Boston University, Boston, MA, 02215, USA.
7
Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA.

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.

KEYWORDS:

Alzheimer's disease; PTPα; estrogen receptor; miR-218; tauopathy

PMID:
26111662
PMCID:
PMC4568974
DOI:
10.1111/acel.12366
[Indexed for MEDLINE]
Free PMC Article

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