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Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of Actaea racemosa.

ABSTRACT: A screen of a library of synthetic drugs and natural product extracts identified a botanical extract that modulates the processing of amyloid precursor protein (APP) in cultured cells to produce a lowered ratio of amyloid-beta peptide (1-42) (A?42) relative to A?40. This profile is of interest as a potential treatment for Alzheimer's disease. The extract, from the black cohosh plant (Actaea racemosa), was subjected to bioassay guided fractionation to isolate active components. Using a combination of normal-phase and reverse-phase chromatography, a novel triterpene monoglycoside, 1, was isolated. This compound was found to have an IC(50) of 100 nM for selectively reducing the production of amyloidogenic A?42 while having a much smaller effect on the production of A?40 (IC(50) 6.3 ?M) in cultured cells overexpressing APP. Using IP-MS methods, this compound was found to modulate the pool of total A? produced by reducing the proportion of A?42 while increasing the relative amounts of shorter and less amyloidogenic A?37 and A?39. Concentrations of 1 sufficient to lower levels of A?42 substantially (up to 10 ?M) did not significantly affect the processing of Notch or other aspects of APP processing. When 1 (10 ?g) was administered to CD-1 normal mice intracerebroventricularly, the level of A?42 in brain was reduced. Assays for off-target pharmacology and the absence of overt signs of toxicity in mice dosed with compound 1 suggest a comparatively selective pharmacology for this triterpenoid. Compound 1 represents a new lead for the development of potential treatments for Alzheimer's disease via modulation of gamma-secretase.

SUBMITTER: Findeis MA

PROVIDER: S-EPMC3509716 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of Actaea racemosa.

Findeis Mark A MA Schroeder Frank F McKee Timothy D TD Yager Debra D Fraering Patrick C PC Creaser Steffen P SP Austin Wesley F WF Clardy Jon J Wang Rong R Selkoe Dennis D Eckman Christopher B CB

ACS chemical neuroscience 20120828 11

A screen of a library of synthetic drugs and natural product extracts identified a botanical extract that modulates the processing of amyloid precursor protein (APP) in cultured cells to produce a lowered ratio of amyloid-beta peptide (1-42) (Aβ42) relative to Aβ40. This profile is of interest as a potential treatment for Alzheimer's disease. The extract, from the black cohosh plant (Actaea racemosa), was subjected to bioassay guided fractionation to isolate active components. Using a combinatio ...[more]

PMID: 23205187

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Project description:BACKGROUND:γ-Secretase is a multiprotein protease that cleaves amyloid protein precursor (APP) and other type I transmembrane proteins. It has two catalytic subunits, presenilins 1 and 2 (PS1 and 2). In our previous report, we observed subtle differences in PS1- and PS2-mediated cleavages of select substrates and slightly different potencies of PS1 versus PS2 inhibition for select γ-secretase inhibitors (GSIs) on various substrates. In this study, we investigated whether γ-secretase modulators (GSMs) and inverse γ-secretase modulators (iGSMs) modulate γ-secretase processivity using multiple different substrates. We next used HEK 293T cell lines in which PSEN1 or PSEN2 was selectively knocked out to investigate processivity and response to GSMs and iGSMs. METHODS:For cell-free γ-secretase cleavage assay, recombinant substrates were incubated with CHAPSO-solubilized CHO or HEK 293T cell membrane with GSMs or iGSMs in suitable buffer. For cell-based assay, cDNA encoding substrates were transfected into HEK 293T cells. Cells were then treated with GSMs or iGSMs, and conditioned media were collected. Aβ and Aβ-like peptide production from cell-free and cell-based assay were measured by ELISA and mass spectrometry. RESULT:These studies demonstrated that GSMs are highly selective for effects on APP, whereas iGSMs have a more promiscuous effect on many substrates. Surprisingly, iGSMs actually appear to act as like GSIs on select substrates. The data with PSEN1 or PSEN2 knocked out HEK 293T reveal that PS1 has higher processivity and response to GSMs than PS2, but PS2 has higher response to iGSM. CONCLUSION:Collectively, these data indicate that GSMs are likely to have limited target-based toxicity. In addition, they show that iGSMs may act as substrate-selective GSIs providing a potential new route to identify leads for substrate-selective inhibitors of certain γ-secretase-mediated signaling events. With growing concerns that long-term β-secretase inhibitor is limited by target-based toxicities, such data supports continued development of GSMs as AD prophylactics.

Dataset Information

Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of Actaea racemosa.

Publications

Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of Actaea racemosa.

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