ß-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aß5-X peptides through alternative amyloid precursor protein cleavage.
Alzheimers Res Ther
; 6(5-8): 75, 2014.
Article
in En
| MEDLINE
| ID: mdl-25404952
ABSTRACT
INTRODUCTION:
The ß-secretase enzyme, ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in ß-amyloid (Aß) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory Aß biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aß1-34 together with increased Aß5-40, suggesting that these Aß species may be novel pharmacodynamic biomarkers in clinical trials. We have now examined whether the same holds true in humans.METHODS:
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 Aß peptides.RESULTS:
Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) Aß1-34, Aß5-40 and Aß5-X after treatment with the BACE1-inhibitor LY2811376. Aß5-40 and Aß5-X increased dose-dependently, as reflected by two independent methods, while Aß1-34 dose-dependently decreased.CONCLUSION:
Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF Aß1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer Aß 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 Aß peptides via a BACE1-independent pathway. TRIAL REGISTRATION ClinicalTrials.gov NCT00838084. Registered First received January 23, 2009, Last updated July 14, 2009, Last verified July 2009.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Clinical_trials
Language:
En
Journal:
Alzheimers Res Ther
Year:
2014
Document type:
Article
Affiliation country:
Sweden
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM