Steroids as γ‐secretase modulators

Abstract

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.

Complex Relationships between Substrate Sequence and Sensitivity to Alterations in γ-Secretase Processivity Induced by γ-Secretase Modulators

“…55 The MI can statistically determine whether a treatment modulates the overall Aβ profile. The MI for each mutant and drug combination is shown in Figure 3A–C.…”

γ-Secretase Processing and Effects of γ-Secretase Inhibitors and Modulators on Long Aβ Peptides in Cells

“…A␤40 and A␤42 were captured with mAb 13.1.1 (human A␤35-40 specific) and mAb 2.1.3 (human A␤35-42 specific), respectively (43,44). Both were detected with HRP-conjugated mAb Ab5 (human A␤1-16 specific) (45).…”

Sex differences in cognitive impairment and Alzheimer’s disease

“…Depletion of estradiol and progesterone result in elevated Aβ levels in transgenic mouse models of AD [95; 122; 140]. Like estrogens, progesterone plays neuroprotective roles in against AD, such as modulating gamma-secretase, another set of enzyme involve Aβ production [141] and increasing Aβ clearance medicated via insulin degradation enzyme (IDE) [142]. Furthermore, studies from human, transgenic mice and cells showed that progesterone also modulates Tau, another pathological molecule in AD and frontotemporal dementia [143].…”

“…Furthermore, studies from human, transgenic mice and cells showed that progesterone also modulates Tau, another pathological molecule in AD and frontotemporal dementia [143]. Unlike estradiol playing a role as an activator of alpha-secretase (an enzyme protecting Aβ production) and an inhibitor of beta-secretase (a key enzyme for Aβ production), progesterone showed no effect on alpha-secretase [141; 144]. Moreover, bioinformatics analysis revealed that progesterone administration in ovariectomized rats was associated with a down-regulation of beta-secretase gene expression [145].…”