Center for Translational Research in Neurodegenerative Disease and Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
FASEB J. 2013 Sep;27(9):3775-85. doi: 10.1096/fj.12-225649. Epub 2013 May 28.
Aggregation and accumulation of Aβ42 play an initiating role in Alzheimer's disease (AD); thus, selective lowering of Aβ42 by γ-secretase modulators (GSMs) remains a promising approach to AD therapy. Based on evidence suggesting that steroids may influence Aβ production, we screened 170 steroids at 10 μM for effects on Aβ42 secreted from human APP-overexpressing Chinese hamster ovary cells. Many acidic steroids lowered Aβ42, whereas many nonacidic steroids actually raised Aβ42. Studies on the more potent compounds showed that Aβ42-lowering steroids were bonafide GSMs and Aβ42-raising steroids were inverse GSMs. The most potent steroid GSM identified was 5β-cholanic acid (EC50=5.7 μM; its endogenous analog lithocholic acid was virtually equipotent), and the most potent inverse GSM identified was 4-androsten-3-one-17β-carboxylic acid ethyl ester (EC50=6.25 μM). In addition, we found that both estrogen and progesterone are weak inverse GSMs with further complex effects on APP processing. These data suggest that certain endogenous steroids may have the potential to act as GSMs and add to the evidence that cholesterol, cholesterol metabolites, and other steroids may play a role in modulating Aβ production and thus risk for AD. They also indicate that acidic steroids might serve as potential therapeutic leads for drug optimization/development.
β淀粉样蛋白（Aβ）42 的聚集和积累在阿尔茨海默病（AD）中起启动作用；因此，通过γ-分泌酶调节剂（GSM）选择性降低 Aβ42 仍然是 AD 治疗的一种有前途的方法。基于类固醇可能影响 Aβ 产生的证据，我们在 10μM 下筛选了 170 种类固醇，以研究它们对人 APP 过表达中国仓鼠卵巢细胞分泌的 Aβ42 的影响。许多酸性类固醇降低了 Aβ42，而许多非酸性类固醇实际上增加了 Aβ42。对更有效化合物的研究表明，降低 Aβ42 的类固醇是真正的 GSM，而升高 Aβ42 的类固醇是反向 GSM。鉴定出的最有效的类固醇 GSM 是 5β-胆酸（EC50=5.7μM；其内源性类似物石胆酸几乎具有同等效力），而鉴定出的最有效的反向 GSM 是 4-雄烯-3-酮-17β-羧酸乙酯（EC50=6.25μM）。此外，我们发现雌激素和孕激素都是较弱的反向 GSM，对 APP 加工有进一步的复杂影响。这些数据表明，某些内源性类固醇可能具有作为 GSM 的潜力，并增加了胆固醇、胆固醇代谢物和其他类固醇可能在调节 Aβ 产生和 AD 风险方面发挥作用的证据。它们还表明，酸性类固醇可能成为药物优化/开发的潜在治疗先导物。
