Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

Background: Amyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.

The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity.

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization.

Steroids as γ-secretase modulators.

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.

Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models".

Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 February 2012) demonstrates short-term bexarotene treatment clearing preexisting β-amyloid deposits from the brains of APP/PS1ΔE9 mice with low amyloid burden, providing a rationale for repurposing this anticancer agent as an Alzheimer's disease (AD) therapeutic.

Cyanobacterial peptides as a prototype for the design of potent β-secretase inhibitors and the development of selective chemical probes for other aspartic proteases.

Inspired by marine cyanobacterial natural products, we synthesized modified peptides with a central statine-core unit, characteristic for aspartic protease inhibition. A series of tasiamide B analogues inhibited BACE1, a therapeutic target in Alzheimer's disease. We probed the stereospecificity of target engagement and determined additional structure-activity relationships with respect to BACE1 and related aspartic proteases, cathepsins D and E.