Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment.
Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment.
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DOI：
10.1523/jneurosci.1180-10.2010
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发表时间：
2010-05-26
期刊：
影响因子：
--
通讯作者：
Li R
中科院分区：
文献类型：
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作者：
McAllister C;Long J;Bowers A;Walker A;Cao P;Honda S;Harada N;Staufenbiel M;Shen Y;Li R
由于脑睾酮通过芳香化酶自然转化为雌激素而同时发挥雄激素和雌激素的作用，目前尚不清楚与年龄相关的睾酮减少增加男性阿尔茨海默病(AD)的风险是通过单独的雄激素还是雄激素和雌激素共同作用的机制。我们之前在小鼠模型中使用基于基因的方法来阻止睾酮转化为雌激素(芳香酶基因敲除，ARKO)，发现在男性体内雌激素消耗和睾酮内源性增加。在这里，我们利用ARKO小鼠与APP23转基因小鼠(AD小鼠模型)杂交，产生APP23/Ar+/−小鼠，以研究睾酮对AD的雌激素非依赖性作用。我们发现，与年龄匹配的雄性APP23对照组相比，雄性APP23/Ar+/−小鼠的脑斑块形成显著减少，认知功能得到改善，NEP活性增加。此外，我们首次在雄性APP23/Ar+/β小鼠中发现了BACE1酶活性、基因水平和蛋白表达的降低，这表明内源性睾酮可能通过两个主要机制对雄性AD起到保护作用，即在转录水平上下调BACE1活性以减少β淀粉样蛋白的产生，以及上调NEP活性以促进BAD淀粉样蛋白的降解。
As brain testosterone plays both androgenic and estrogenic actions due to its conversion into estrogen via aromatase naturally, it is unclear that the age-related reduction of testosterone increased risk of Alzheimer’s disease (AD) in men is mediated through androgen alone or both androgen and estrogen mechanisms. Our previous studies using a gene-based approach in mouse model to block the conversion of testosterone into estrogen (aromatase gene knock-out, ArKO), found a depletion of estrogen and increase in testosterone endogenously in males. Here, we use crossing the ArKO mice with APP23 transgenic mice, a mouse model of AD, to produce APP23/Ar+/− mice to study the estrogen-independent effect of testosterone on AD. We found a significant reduction in brain plaque formation, improved cognitive function and increase NEP activity in male APP23/Ar+/− mice compared with age-matched male APP23 controls. In addition, we found, for the first time, a reduction of β-secretase (BACE1) enzyme activity, mRNA level and protein expression in the male APP23/Ar+/− mice, suggesting that endogenous testosterone, independent from estrogen, may protect against AD in males via two major mechanisms, downregulation of BACE1 activities at transcriptional level to reduce β amyloid production and upregulation of NEP activities to enhance bate amyloid degradation.