PXD067413

PXD067413 is an original dataset announced via ProteomeXchange.

Title	Elenbecestat and compound 89 potently inhibit BACE1 but not BACE2 when subchronically dosed in non-human primates
Description	The 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.
HostingRepository	PRIDE
AnnounceDate	2025-11-07
AnnouncementXML	Submission_2025-11-07_03:24:37.333.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Karsten Nalbach
SpeciesList	scientific name: Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey); NCBI TaxID: NEWT:9541;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-16 03:53:49	ID requested
⏵ 1	2025-11-07 03:24:37	announced

Dataset with its publication pending

submitter keyword: proteomics,CSF, BACE1 inhibition, NHP, LC-MS/MS

Stefan F. Lichtenthaler
contact affiliation	DZNE Munich / TU Munich
contact email	stefan.lichtenthaler@dzne.de
lab head
Karsten Nalbach
contact affiliation	DZNE Munich / TU Munich
contact email	karsten.nalbach@dzne.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067413
     1. Label: PRIDE project
     2. Name: Elenbecestat and compound 89 potently inhibit BACE1 but not BACE2 when subchronically dosed in non-human primates