PLoS ONE (Jan 2012)

BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system.

  • Niklas Mattsson,
  • Lawrence Rajendran,
  • Henrik Zetterberg,
  • Mikael Gustavsson,
  • Ulf Andreasson,
  • Maria Olsson,
  • Gunnar Brinkmalm,
  • Johan Lundkvist,
  • Laura H Jacobson,
  • Ludovic Perrot,
  • Ulf Neumann,
  • Herman Borghys,
  • Marc Mercken,
  • Deborah Dhuyvetter,
  • Fredrik Jeppsson,
  • Kaj Blennow,
  • Erik Portelius

DOI
https://doi.org/10.1371/journal.pone.0031084
Journal volume & issue
Vol. 7, no. 2
p. e31084

Abstract

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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.