PXD056159

PXD056159 is an original dataset announced via ProteomeXchange.

Title	Soluble VCAM-1 may serve as a pharmacodynamic CSF marker to monitor BACE2 activity in non-human primates
Description	The beta-secretase beta-site APP cleaving enzyme 1 (BACE1) is a major drug target for Alzheimer’s disease (AD). Clinically tested BACE1 inhibitors induced unexpected cognitive side effects that may stem from their cross-inhibition of the homologous protease BACE2. Yet, little is known about BACE2 functions and substrates in vivo and no biomarker is available allowing to monitor the extent of BACE2 inhibition in vivo, in particular in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes of non-human primates after treatment with a BACE1-selective inhibitor (a brain-targeted monoclonal antibody) in comparison to verubecestat, a clinically tested small molecule drug inhibiting both BACE1 and BACE2. Acute treatment with either the antibody or verubecestat similarly reduced CSF abundance of the cleavage products of several known BACE1 substrates, including SEZ6, gp130 and CACHD1, demonstrating similar target engagement in vivo. One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD.
HostingRepository	PRIDE
AnnounceDate	2025-07-16
AnnouncementXML	Submission_2025-07-16_03:50:57.188.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stephan Mueller
SpeciesList	scientific name: Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey); NCBI TaxID: 9541;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-24 02:45:57	ID requested
⏵ 1	2025-07-16 03:50:57	announced

Tschirner SK, Zuchero YJY, Getz JA, M, ü, ller SA, Nalbach K, Kennedy ME, Lewcock JW, Lichtenthaler SF, Soluble VCAM-1 May Serve as a Pharmacodynamic CSF Marker to Monitor BACE2 Activity in Non-Human Primates. Mol Cell Proteomics, 24(7):101012(2025) [pubmed]

10.1016/j.mcpro.2025.101012;

submitter keyword: DIA,Cerebrospinal Fluid, Alzheimer's disease, CSF, BACE1, Macaca fascicularis, labelfree, VCAM1

Stefan Lichtenthaler
contact affiliation	DZNE Munich, Neuroproteomics, Feodor-Lynen-Str. 17, 81377 München, Germany
contact email	stefan.lichtenthaler@dzne.de
lab head
Stephan Mueller
contact affiliation	DZNE Munich Neuroproteomics
contact email	stephan.mueller@dzne.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/07/PXD056159

PRIDE project URI

• PRIDE
  1. PXD056159
     1. Label: PRIDE project
     2. Name: Soluble VCAM-1 may serve as a pharmacodynamic CSF marker to monitor BACE2 activity in non-human primates