Steroids as γ‐secretase modulators

Aggregation and accumulation of Aβ 42 play an initiating role in Alzheimer's disease (AD); thus, selective lowering of Aβ 42 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 Aβ 42 secreted from human APP‐overexpressing Chinese hamster ovary cells. Many acidic steroids lowered Aβ 42 , whereas many nonacidic steroids actually raised Aβ 42 . Studies on the more potent compounds showed that Aβ 42 ‐lowering steroids were bonafide GSMs and Aβ 42 ‐raising steroids were inverse GSMs. The most potent steroid GSM identified was 5β‐cholanic acid (EC 50 =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 (EC 50 =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.—Jung, J. I., Ladd, T. B., Kukar, T., Price, A. R., Moore, B. D., Koo, E. H., Golde, T. E., Felsenstein, K. M., Steroids as γ‐secretase modulators. FASEB J. 27, 3775–3785 (2013). www.fasebj.org