The Effect And Mechanism Of Estrogen In Alzheimer-like Tau Protein Of Phosphorylation

Alzheimer's disease (AD) is a neurodegenerative disorder defined by progressive memoryloss and cognitive impairment and at the molecularlevel bythe presence of neurofibrillarytangles (NFTs) and insolubleβ-amyloid (Aβ) plaque. Risk for Alzheimer's disease isassociated with age-related loss of estrogen in both women and men. In post-menopausalwomen, the precipitous depletion of estrogens is hypothesized to increase susceptibility toAD pathogenesis, a concept largely supported by epidemiological evidence and basicresearch.But the underlying mechanism still needs investigation.Estrogen, mainlythroughthe role of estrogen receptor andincludingestrogen receptor ?and?.Wepreviouslyfoundestrogen could reduce tau hyperphosphorylation by inhibiting glycogen synthase kinase-3(GSK-3), a major tau phosphorylation-related kinase. It has two highly homologous formsof GSK-3 in mammal, GSK-3αand GSK-3β.This mention us there is a relationshipbetween estrogen receptor and GSK-3. In this research the levels of estrogen receptors(ER?and ER?) and GSK-3 were investigated in ovariectomized rat brain of eight differenttime points at early stage after operation. Methods: We ovariectmized (OVX) SD rats toestablish animal mode of low estrogen level. Expressions of estrogen receptor andGSK-3weredetectedat0,1,2,4,8,12,16,24weekafteroperationbyimmunohistochemistryandWesternblots.Results: WefoundthatER?graduallyreducedwithtime. In particular4,8,12weekafterovariectomy.MeanwhilephosphorylationofER?at Ser118siteandthetotal level of GSK3αand GSK3βwas increased. There is no alteration of ER?level in the earlystage of ovariectomy. Immunohistochemistrical data showed that the distribution of ERαandERαS118graduallyshiftfromthecytoplasmtothenucleusinhippocampalCA1regionafter ovariectomy.Meanwhile GSK-3 is mainlydistributed in the cytoplasm. Conclusions:These data indicated that in a particular time increased phosphorylation of ER?might beinvolved in over-expression of GSK-3?in the brain of OVX rats. ER?might be moreimportantthanER?toeffecttheincreasingofGSK-3?intheearlystageofovariectomy.