Dataset Information

Estrogen stimulates degradation of beta-amyloid peptide by up-regulating neprilysin.

ABSTRACT: Postmenopausal estrogen depletion is a characterized risk factor for Alzheimer disease (AD), a human disorder linked to high levels of beta-amyloid peptide (Abeta) in brain tissue. Previous studies suggest that estrogen negatively regulates the level of Abeta in the brain, but the molecular mechanism is unknown. Here, we provide evidence that estrogen promotes Abeta degradation mainly through a principal Abeta degrading enzyme, neprilysin, in neuroblastoma SH-SY5Y cells. We also demonstrate that up-regulation of neprilysin by estrogen is dependent on both estrogen receptor alpha and beta (ERalpha and ERbeta), and ligand-activated ER regulates expression of neprilysin through physical interactions between ER and estrogen response elements (EREs) identified in the neprilysin gene. These results were confirmed by in vitro gel shift and in vivo chromatin immunoprecipitation analyses, which demonstrate specific binding of ERalpha and ERbeta to two putative EREs in the neprilysin gene. The EREs also enhance ERalpha- and ERbeta-dependent reporter gene expression in a yeast model system. Therefore, the study described here provides a putative mechanism by which estrogen positively regulates expression of neprilysin to promote degradation of Abeta, reducing risk for AD. These results may lead to novel approaches to prevent or treat AD.

SUBMITTER: Liang K

PROVIDER: S-EPMC2801294 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Estrogen stimulates degradation of beta-amyloid peptide by up-regulating neprilysin.

Liang Kaiwei K Yang Liuqing L Yin Chen C Xiao Zhimin Z Zhang Junjian J Liu Yumin Y Huang Jian J

The Journal of biological chemistry 20091106 2

Postmenopausal estrogen depletion is a characterized risk factor for Alzheimer disease (AD), a human disorder linked to high levels of beta-amyloid peptide (Abeta) in brain tissue. Previous studies suggest that estrogen negatively regulates the level of Abeta in the brain, but the molecular mechanism is unknown. Here, we provide evidence that estrogen promotes Abeta degradation mainly through a principal Abeta degrading enzyme, neprilysin, in neuroblastoma SH-SY5Y cells. We also demonstrate that ...[more]

PMID: 19897485

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Project description:Background: Aggregation of the amyloid-beta (Aβ) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading Aβ, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients. The poor delivery of SST over the blood-brain barrier (BBB) and its extremely short half-life of only 3 min limit its therapeutic significance. Methods: We recombinantly fused SST to a BBB transporter binding to the transferrin receptor. Using primary neuronal cultures and neuroblastoma cell lines, the ability of the formed fusion protein to activate neprilysin was studied. SST-scFv8D3 was administered to mice overexpressing the Aβ-precursor protein (AβPP) with the Swedish mutation (APPswe) as a single injection or as a course of three injections over a 72 h period. Levels of neprilysin and Aβ were quantified using an Enzyme-linked immunosorbent assay (ELISA). Distribution of SST-scFv8D3 in the brain, blood and peripheral organs was studied by radiolabeling with iodine-125. Results: The construct, SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously and significantly increased the brain concentration of neprilysin in APPswe mice. A significant decrease in the levels of membrane-bound Aβ42 was detected in the hippocampus and the adjacent cortical area after only three injections. Conclusion: With intravenous injections of our BBB permeable SST peptide, we were able to significantly increase the levels neprilysin, an effect that was followed by a significant and selective degradation of membrane-bound Aβ42 in the hippocampus. Being that membrane-bound Aβ triggers neuronal toxicity and the hippocampus is the central brain area in the progression of AD, the study has illuminated a new potential treatment paradigm with a promising safety profile targeting only the disease affected areas.

Dataset Information

Estrogen stimulates degradation of beta-amyloid peptide by up-regulating neprilysin.

Publications

Estrogen stimulates degradation of beta-amyloid peptide by up-regulating neprilysin.

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