Soluble VCAM-1 May Serve as a Pharmacodynamic CSF Marker to Monitor BACE2 Activity in Non-Human Primates

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• BACE1 is a key drug target for Alzheimer's disease (AD).
• BACE1 inhibitors can cause cognitive side effects due to cross-inhibition of BACE2.
• Lack of a biomarker to monitor BACE2 inhibition in cerebrospinal fluid (CSF).

Purpose of the Study:

• To identify a CSF biomarker for monitoring BACE2 activity.
• To evaluate VCAM-1 as a potential biomarker for BACE2 inhibition.

Main Methods:

• Analysis of CSF proteome changes in non-human primates.
• Comparison of a BACE1-selective inhibitor (monoclonal antibody) with a dual BACE1/BACE2 inhibitor (verubecestat).

Main Results:

• Both inhibitors reduced CSF levels of known BACE1 substrates (SEZ6, gp130, CACHD1).
• VCAM-1 levels were reduced only by the dual inhibitor (verubecestat), not the BACE1-selective inhibitor.
• VCAM-1 is identified as a candidate biomarker for BACE2 inhibition.

Conclusions:

• VCAM-1 is a promising CSF biomarker for monitoring BACE2 inhibition.
• This finding aids in developing BACE1-selective inhibitors for AD prevention.
• Understanding BACE2 function is critical for AD therapeutic strategies.