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- Title
BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system.
- Authors
Mattsson, Niklas; Rajendran, Lawrence; Zetterberg, Henrik; Gustavsson, Mikael; Andreasson, Ulf; Olsson, Maria; Brinkmalm, Gunnar; Lundkvist, Johan; Jacobson, Laura H; Perrot, Ludovic; Neumann, Ulf; Borghys, Herman; Mercken, Marc; Dhuyvetter, Deborah; Jeppsson, Fredrik; Blennow, Kaj; Portelius, Erik
- Abstract
BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides, analyzed in cell media from amyloid precursor protein (APP) transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1-40 and Aβ1-42, treatment also changed the relative levels of several other Aβ isoforms. In particular Aβ1-34 decreased, while Aβ5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in Aβ1-40 and Aβ1-42. The effects on Aβ5-40 indicate the presence of a BACE1 independent pathway of APP degradation. The described CSF Aβ pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.
- Publication
PloS one, 2012, Vol 7, Issue 2, pe31084
- ISSN
1932-6203
- Publication type
Journal Article
- DOI
10.1371/journal.pone.0031084