TY  - JOUR
AU  - Tschirner, Sarah K
AU  - Zuchero, Y Joy Yu
AU  - Getz, Jennifer A
AU  - Müller, Stephan A
AU  - Nalbach, Karsten
AU  - Kennedy, Matthew E
AU  - Lewcock, Joseph W
AU  - Lichtenthaler, Stefan F
TI  - Soluble VCAM-1 May Serve as a Pharmacodynamic CSF Marker to Monitor BACE2 Activity in Non-Human Primates.
JO  - Molecular & cellular proteomics
VL  - 24
IS  - 7
SN  - 1535-9476
CY  - Bethesda, Md.
PB  - The American Society for Biochemistry and Molecular Biology
M1  - DZNE-2025-00944
SP  - 101012
PY  - 2025
AB  - The β-secretase β-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 to monitor the extent of BACE2 inhibition in vivo, particularly in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes in 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.
KW  - Animals
KW  - Amyloid Precursor Protein Secretases: antagonists & inhibitors
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Amyloid Precursor Protein Secretases: cerebrospinal fluid
KW  - Aspartic Acid Endopeptidases: antagonists & inhibitors
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Aspartic Acid Endopeptidases: cerebrospinal fluid
KW  - Biomarkers: cerebrospinal fluid
KW  - Vascular Cell Adhesion Molecule-1: cerebrospinal fluid
KW  - Antibodies, Monoclonal: pharmacology
KW  - Humans
KW  - Male
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - Vascular Cell Adhesion Molecule-1 (NLM Chemicals)
KW  - Antibodies, Monoclonal (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40480341
C2  - pmc:PMC12280488
DO  - DOI:10.1016/j.mcpro.2025.101012
UR  - https://pub.dzne.de/record/280289
ER  -