Estrogen, androgen, neprilysin, and amyloid peptides.

描述(申请人提供)：模型研究表明，在小鼠中，卵巢切除会增加淀粉样蛋白B(AB)肽的水平，而卵巢切除后再进行雌激素替代会将AB肽的浓度降低到正常或低于正常水平。我们最近发现，去卵巢会导致大鼠脑内Neprilysin多肽酶活性降低，而去卵巢后雌激素替代会增加脑组织neprilysin基因转录和neprilysin酶活性。Neprilysin已被证明是主要的，或主要的酶之一，参与AB肽清除在大脑中。因此，我们推测雌激素耗竭提高AB肽水平和雌激素替代降低AB肽水平的效果至少部分是由于雌激素对neprilysin活性的影响。同样，最近有研究表明，性腺切除会增加大鼠的AB肽水平，而雄激素替代可逆转这一效应。由于neprilysin基因也受雄激素的调节，我们推测，性腺切除和雄激素替代对AB肽水平的影响也是通过对neprilysin基因的影响而实现的。为了验证这一假设，我们提出了两个具体目标：(1)我们将比较雌激素在降低含有瑞典和印第安纳州突变的人淀粉样前体蛋白突变基因的小鼠(J20小鼠系)中的AB肽水平的效果，与雌激素对J20小鼠与neprilysin基因敲除小鼠以及J20小鼠与雌激素受体基因敲除小鼠杂交的影响进行比较。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的Neprilysin活性增加的结果，以及是否雌激素受体依赖性机制导致雄激素耗竭增加AB肽水平和雄激素替代降低AB肽水平的报道是由于雄激素对neprilysin的作用。 利用小鼠模型，我们将确定类固醇激素对AB肽水平的影响是否是它们对neprilysin活性影响的结果，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病药物开发的靶点。

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.