title: Opposite effects of two estrogen receptors on tau phosphorylation through disparate effects on the miR-218/PTPA pathway.
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.
authors.affiliation: 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.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Yan-Si
authors.initials: YS
authors.lastname: Xiong
authors.affiliation: 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.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Liu
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.|Department of Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: 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.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: He-Zhou
authors.initials: HZ
authors.lastname: Huang
authors.affiliation: 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.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: 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.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Tan
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.|Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
authors.affiliation: Department of Biology, Boston University, Boston, MA, 02215, USA.
authors.forename: Heng-Ye
authors.initials: HY
authors.lastname: Man
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA.
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Youming
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 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.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: 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.|The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.|Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D016875:tau Proteins; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4
keywords: Alzheimer's disease; PTPα; estrogen receptor; miR-218; tauopathy