biostudies-literatureToyn JHNCATS NIH HHS125-37https://www.ebi.ac.uk/biostudies/studies/S-EPMC4931879biostudies-literatureUnknown358(1)The amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substraThe Journal of pharmacology and experimental therapeuticsRobust Translation of γ-Secretase Modulator Pharmacology across Preclinical Species and Human Subjects.PMC4931879UL1 TR001863Zuev DClarke WGasior MPadmanabha RBerisha FFurlong MRaybon JOlson REDrexler DMZhuo XBoy KMLentz KAWang JSWei CDenton RRGuss VSnow KGrace JSweeney FAhlijanian MKRobertson ASMorrison JCook LHoque NAbuTarif MThompson LAMeredith JESoares HDAlbright CFHong QToyn JHMacor JEfalseRobust Translation of γ-Secretase Modulator Pharmacology across Preclinical Species and Human Subjects.The amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substra2016-01-01T00:00:00Z2016 Jul2026-05-05T15:05:50.762Z2019-03-27T02:17:31ZS-EPMC49318792718997410.1124/jpet.116.232249