Estrogen, androgen, neprilysin, and amyloid peptides.

描述（由申请人提供）：模型研究表明，在小鼠中，卵巢切除术增加淀粉样蛋白B（AB）肽水平，而卵巢切除术后雌激素替代降低AB肽浓度至正常或低于正常水平。 我们最近发现，大鼠卵巢切除导致肽酶脑啡肽酶的活性降低，而卵巢切除后雌激素替代增加脑啡肽酶基因转录和脑啡肽酶酶活性。 脑啡肽酶已被证明是参与脑中AB肽清除的主要酶或主要酶之一。 因此，我们假设，雌激素耗竭的影响，提高AB肽水平和雌激素替代降低AB肽水平的发生，至少部分，作为一个结果，雌激素对脑啡肽酶活性的影响。 类似地，最近已经表明，性腺切除术增加大鼠中AB肽水平，雄激素替代逆转了这种作用。 由于脑啡肽酶基因也受雄激素的调节，我们推测性腺切除术和雄激素替代对AB肽水平的影响也是通过对脑啡肽酶基因的影响介导的。 提出了两个具体目的来检验这一假设：（1）我们将比较雌激素在表达含有瑞典和印第安纳州突变的突变型人淀粉样前体蛋白的小鼠（J20小鼠系）中降低AB肽水平的作用与雌激素在与脑啡肽酶敲除小鼠杂交的J20小鼠和与雌激素受体敲除小鼠杂交的J20小鼠中的作用。 这些实验将确定AB肽水平的雌激素依赖性降低是否是脑啡肽酶活性的雌激素依赖性增加的结果，以及雌激素受体依赖性机制是否负责所报道的雄激素耗竭增加AB肽水平的作用，以及雄激素替代降低AB肽水平是由于雄激素对脑啡肽酶的作用。 使用小鼠模型，我们将确定类固醇激素介导的AB肽水平的影响是否是由于它们对脑啡肽酶活性的影响，以及类固醇激素或其选择性受体调节剂是否可以作为开发预防阿尔茨海默病的药物的靶点。

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.