Home > Publications Database > Soluble VCAM-1 May Serve as a Pharmacodynamic CSF Marker to Monitor BACE2 Activity in Non-Human Primates. > print

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024 7 _ |a 10.1016/j.mcpro.2025.101012
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041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Tschirner, Sarah K
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245 _ _ |a Soluble VCAM-1 May Serve as a Pharmacodynamic CSF Marker to Monitor BACE2 Activity in Non-Human Primates.
260 _ _ |a Bethesda, Md.
|c 2025
|b The American Society for Biochemistry and Molecular Biology
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520 _ _ |a 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.
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650 _ 7 |a Amyloid Precursor Protein Secretases
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650 _ 7 |a Aspartic Acid Endopeptidases
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650 _ 7 |a Biomarkers
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650 _ 7 |a Vascular Cell Adhesion Molecule-1
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650 _ 7 |a Antibodies, Monoclonal
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650 _ 2 |a Animals
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650 _ 2 |a Amyloid Precursor Protein Secretases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: metabolism
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: cerebrospinal fluid
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650 _ 2 |a Aspartic Acid Endopeptidases: antagonists & inhibitors
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650 _ 2 |a Aspartic Acid Endopeptidases: metabolism
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Biomarkers: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Vascular Cell Adhesion Molecule-1: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Antibodies, Monoclonal: pharmacology
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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Male
|2 MeSH
700 1 _ |a Zuchero, Y Joy Yu
|b 1
700 1 _ |a Getz, Jennifer A
|b 2
700 1 _ |a Müller, Stephan A
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700 1 _ |a Nalbach, Karsten
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700 1 _ |a Kennedy, Matthew E
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700 1 _ |a Lewcock, Joseph W
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700 1 _ |a Lichtenthaler, Stefan F
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773 _ _ |a 10.1016/j.mcpro.2025.101012
|g Vol. 24, no. 7, p. 101012 -
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|t Molecular & cellular proteomics
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856 4 _ |u https://pub.dzne.de/record/280289/files/DZNE-2025-00944%20SUP.zip
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