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000280289 1001_ $$0P:(DE-2719)9000794$$aTschirner, Sarah K$$b0$$eFirst author$$udzne
000280289 245__ $$aSoluble VCAM-1 May Serve as a Pharmacodynamic CSF Marker to Monitor BACE2 Activity in Non-Human Primates.
000280289 260__ $$aBethesda, Md.$$bThe American Society for Biochemistry and Molecular Biology$$c2025
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000280289 520__ $$aThe 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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000280289 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000280289 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000280289 650_7 $$2NLM Chemicals$$aBiomarkers
000280289 650_7 $$2NLM Chemicals$$aVascular Cell Adhesion Molecule-1
000280289 650_7 $$2NLM Chemicals$$aAntibodies, Monoclonal
000280289 650_2 $$2MeSH$$aAnimals
000280289 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: antagonists & inhibitors
000280289 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000280289 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: cerebrospinal fluid
000280289 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: antagonists & inhibitors
000280289 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: metabolism
000280289 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: cerebrospinal fluid
000280289 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000280289 650_2 $$2MeSH$$aVascular Cell Adhesion Molecule-1: cerebrospinal fluid
000280289 650_2 $$2MeSH$$aAntibodies, Monoclonal: pharmacology
000280289 650_2 $$2MeSH$$aHumans
000280289 650_2 $$2MeSH$$aMale
000280289 7001_ $$aZuchero, Y Joy Yu$$b1
000280289 7001_ $$aGetz, Jennifer A$$b2
000280289 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b3$$udzne
000280289 7001_ $$0P:(DE-2719)9002811$$aNalbach, Karsten$$b4$$udzne
000280289 7001_ $$aKennedy, Matthew E$$b5
000280289 7001_ $$aLewcock, Joseph W$$b6
000280289 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b7$$eLast author$$udzne
000280289 773__ $$0PERI:(DE-600)2071375-7$$a10.1016/j.mcpro.2025.101012$$gVol. 24, no. 7, p. 101012 -$$n7$$p101012$$tMolecular & cellular proteomics$$v24$$x1535-9476$$y2025
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