000282934 001__ 282934
000282934 005__ 20251218141032.0
000282934 037__ $$aDZNE-2025-01395
000282934 1001_ $$0P:(DE-2719)9002811$$aNalbach, Karsten$$b0$$udzne
000282934 245__ $$aDataset: Elenbecestat and compound 89 potently inhibit BACE1 but not BACE2 when subchronically dosed in non-human primates (Project PXD067413)
000282934 260__ $$bPRoteomics IDEntifications Database$$c2025
000282934 3367_ $$2BibTeX$$aMISC
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000282934 520__ $$aThe beta-secretase BACE1 (beta-site amyloid precursor (APP)-cleaving enzyme 1) is a major drug target for Alzheimer’s disease (AD), as it catalyzes the first step in amyloid beta (Abeta) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.
000282934 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
000282934 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan$$b1$$udzne
000282934 8564_ $$uhttps://wwwdev.ebi.ac.uk/pride/archive/projects/PXD067413
000282934 909CO $$ooai:pub.dzne.de:282934$$pVDB
000282934 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)9002811$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000282934 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2181459$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b1$$kDZNE
000282934 9131_ $$0G:(DE-HGF)POF4-352$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vDisease Mechanisms$$x0
000282934 9141_ $$y2025
000282934 9201_ $$0I:(DE-2719)1110006$$kAG Lichtenthaler$$lNeuroproteomics$$x0
000282934 980__ $$adataset
000282934 980__ $$aVDB
000282934 980__ $$aI:(DE-2719)1110006
000282934 980__ $$aUNRESTRICTED