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

Abstract

BackgroundAmyloid-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 5.7 μM.ResultsWe find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1−/−) and Cyp7b1 knockout (Cyp7b1−/−) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1−/− had increased brain Aβ42, whereas Cyp7b1−/− mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency.ConclusionThese data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0021-z) contains supplementary material, which is available to authorized users.

Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions

“…Previous studies have shown that diverse compounds, referred to as g-secretase inverse modulators, mimic FAD-linked mutations by enhancing Ab 42 generation from the wild-type enzyme (Kukar et al, 2005). In contrast, g-secretase modulators (GSMs) (Weggen et al, 2001), including endogenous metabolites (Jung et al, 2015), enhance protease processivity (Chávez-Gutié rrez et al, 2012;Takeo et al, 2014). However, their mechanisms of action have remained elusive.…”

Implications of GABAergic Neurotransmission in Alzheimer’s Disease

“…In amyloidogenic processing, APP is first cleaved by β-secretase (beta-site APP cleaving enzyme 1, BACE1), releasing a soluble ectodomain called sAPPβ. The remaining membrane associated carboxyl terminal fragment (βCTF) will be further cleaved by γ-secretase within the cell membrane, releasing neurotoxic Aβ peptides and amyloid intracellular domain (AICD; Li et al, 2014 ; Ohki et al, 2014 ; Jung et al, 2015 ; Neumann et al, 2015 ; Sadleir et al, 2015 ; Zhang et al, 2015 ). The exact cleavage site of γ-secretase may vary inside membrane, yielding Aβ peptides with 36–43 amino acids.…”

The Cholesteryl Ester Transfer Protein (CETP) raises Cholesterol Levels in the Brain and affects Presenilin-mediated Gene Regulation

“…First, the ectodomain of APP is removed by βsecretase and then the membrane-bound C-terminal fragment is cleaved by γ-secretase (71)(72)(73). It is well established that higher cellular levels of cholesterol stimulate β-and γ-secretase activity (74)(75)(76)(77)(78).…”