?-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces A?5-X peptides through alternative amyloid precursor protein cleavage.

ABSTRACT: The ?-secretase enzyme, ?-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in ?-amyloid (A?) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory A? biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of A?1-34 together with increased A?5-40, suggesting that these A? species may be novel pharmacodynamic biomarkers in clinical trials. We have now examined whether the same holds true in humans.In an investigator-blind, placebo-controlled and randomized study, healthy subjects (n =18) were randomly assigned to receive a single dose of 30 mg of LY2811376 (n =6), 90 mg of LY2811376 (n =6), or placebo (n =6). We used hybrid immunoaffinity-mass spectrometry (HI-MS) and enzyme-linked immunosorbent assays to monitor a variety of A? peptides.Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) A?1-34, A?5-40 and A?5-X after treatment with the BACE1-inhibitor LY2811376. A?5-40 and A?5-X increased dose-dependently, as reflected by two independent methods, while A?1-34 dose-dependently decreased.Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF A?1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer A? species, it is less susceptible to preanalytical confounding factors and may thus be a more stable marker. By independent measurement techniques, we also show that BACE1 inhibition in humans is associated with APP-processing into N-terminally truncated A? peptides via a BACE1-independent pathway.ClinicalTrials.gov NCT00838084. Registered: First received: January 23, 2009, Last updated: July 14, 2009, Last verified: July 2009.

SUBMITTER: Portelius E 

PROVIDER: S-EPMC4233234 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature