Estrogen, androgen, neprilysin, and amyloid peptides.

雌激素、雄激素、脑啡肽酶和淀粉样肽。

基本信息

批准号：
7340690
负责人：
Louis B. Hersh
金额：
$ 22.49万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2010-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Model studies have shown that in mice, ovariectomy increases amyloid B (AB) peptide levels, while ovariectomy followed by estrogen replacement lowers the concentration of AB peptides to normal or below normal levels. We recently found that ovariectomy in rats leads to a decrease in the activity of the peptidase neprilysin, and that ovariectomy followed by estrogen replacement increases neprilysin gene transcription and neprilysin enzyme activity in the brain. Neprilysin has been shown to be the major, or one of the major enzymes involved in AB peptide clearance in the brain. We thus postulate that the effect of the estrogen depletion in raising AB peptide levels and estrogen replacement in lowering AB peptide levels occurs, at least in part, as a result of estrogen effects on neprilysin activity. Similarly, it has recently been shown that gonadectomy increases AB peptide levels in rats, and androgen replacement reverses this effect. Since the neprilysin gene is also regulated by androgens, we speculate that the effect of gonadectomy and androgen replacement on AB peptide levels is also mediated through effects on the neprilysin gene. Two Specific Aims are proposed to test this hypothesis: (1) we will compare the effect of estrogen in reducing AB peptide levels in mice expressing a mutant human amyloid precursor protein containing the Swedish and Indiana mutations (J20 mouse line) to the effect of estrogen in the J20 mouse crossed with a neprilysin knockout mouse, and the J20 mouse crossed with an estrogen receptor knockout mouse. These experiments will establish whether the estrogen dependent decreases in AB peptide levels is a result of the estrogen dependent increased in neprilysin activity and whether an estrogen receptor dependent mechanism is responsible for reported effect of androgen depletion increasing AB peptide levels and androgen replacement lowering AB peptide levels is due to androgen effects on neprilysin. Using mouse models we will determine whether steroid hormone mediated effects on AB peptide levels are a result of their affects on neprilysin activity and whether steroid hormones or their selective receptor modulators can serve as a target for the development of drugs for the prevention of Alzheimer's disease.

描述（由申请人提供）：模型研究表明，在小鼠中，卵巢切除术会增加淀粉样蛋白B（AB）肽水平，而卵巢切除术则促进了雌激素替代，将AB肽的浓度降低至正常水平或低于正常水平。我们最近发现，大鼠的卵巢切除术会导致肽酶Neprilysin的活性降低，而卵巢切除术随后雌激素替代增加了Neprilysin基因转录和大脑中的Neprilysin酶活性。 Neprilysin已被证明是参与大脑中AB肽清除率的主要酶之一。因此，我们假设雌激素耗竭在降低AB肽水平中升高AB肽水平和雌激素替代方面的作用至少部分是由于雌激素对Neprilysin对Neprilysin活性的影响。同样，最近已经表明，雌激素替代的腺切除术会增加大鼠的AB肽水平，而雄激素替代会逆转这种作用。由于Neprilysin基因也受雄激素的调节，因此我们推测，促性腺切除术和雄激素替代对AB肽水平的影响也通过对Neprilysin基因的影响介导。提出了两个具体的目的来检验这一假设：（1）我们将比较雌激素在降低AB肽水平中的效果，表达含有瑞典的突变体淀粉样蛋白前体蛋白（J20小鼠）与Neprilysin hocking鼠标的J20小鼠交叉的雌激素的效果，并与雌激素的效果与J20 Ountior houndeor houndeor houndeor hockout hounder hounder hounder hounder hounder hounder hounder hounder hounder hounder hounder hounder houndef houndef houndef鼠标。这些实验将确定雌激素依赖性的AB肽水平降低是否是雌激素依赖性在Neprilysin活性中增加的结果，以及雌激素受体依赖性机制是否导致报告的雄激素耗竭的影响增加了AB肽水平，而雄激素替代的AB肽水平降低了AB肽水平，从而对Neprilysagen的影响降低了。使用小鼠模型，我们将确定类固醇激素介导的对AB肽水平的作用是否是它们对Neprilysin活性的影响以及类固醇激素或其选择性受体调节剂是否可以作为预防阿尔茨海默氏病的药物的靶标。