Abstract
The female predominance for developing Alzheimer disease (AD) suggests the involvement of gender specific factor(s) such as a reduced estrogen-estrogen receptor signaling in the pathogenesis of AD. The potential role of ERα in AD pathogenesis has been explored by several groups with mixed results. We revisited this issue of expression and distribution of ERα in AD brain using a specific ERα antibody. Interestingly, we found that ERα co-localized with neurofibrillary pathology in AD brain and further demonstrated that ERα interacts with tau protein in vivo. Immunoprecipitaion experiments found increased ERα-tau interaction in the AD cases, which may account for ERα being sequestered in neuronal tau pathology. Indeed, tau overexpression in M17 cells leads to interruption of estrogen signaling. Our data support the idea that sequestration of ERα by tau pathology underlies the loss of estrogen neuroprotection during the course of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by selective neuronal loss in the hippocampus and temporal cortex along with distinctive hallmark pathologies such as neurofibrillary tangles (NFTs) and senile plaques[1,2]
To confirm the localization of estrogen receptor α (ERα) in NFTs, double fluorescence staining with antibodies to ERα and hyperphosphorylated tau (PHF-1) revealed that ERα -positive NFTs were positive for paired helical filaments (PHF)-1 (Fig. 2A–F)
We focused on the distribution of ERα as it relates to tau alterations in the hippocampus and cortex of Alzheimer disease (AD) patient brains and reported several novel findings: 1) for the first time, we found that ERα is localized to neurofibrillary tangles in AD brain with nearly complete overlap with hyperphosphorylated tau as marked by PHF-1 antibody; 2) there is no significant difference in the expression of ERα between AD and control as shown by western blot analysis; 3) ERα co-purifies with paired helical filaments (PHFs) prepared from AD brain homogenates; 4) ERα interacts with tau proteins in vivo and there is increased ERα -tau interaction in AD brain
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by selective neuronal loss in the hippocampus and temporal cortex along with distinctive hallmark pathologies such as neurofibrillary tangles (NFTs) and senile plaques[1,2]. Estrogen loss in menopausal women has been suspected to be closely related with the occurrence of AD8 Along this line, some clinical and experimental studies supported a preventive role of estrogen replacement therapy in cognitive deterioration-related disease, such as AD9, it should be noted that several other studies failed to replicate such beneficial effects[10]. While estrogen decreases the hyperphosphorylation of tau in a ER-dependent manner[43] supporting the observation that females have more affected brain regions with NFTs than males[44] and show more severe early tau alterations in the nucleus basalis of Meynert[45], a recent study demonstrated that overexpression of ERα caused tau hyperphosphorylation and aggregation[46]. We revisit the issue of expression and distribution of ERα in specific AD brain regions (i.e., hippocampus and cortex) with a focus on its relationship with tau alterations.
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