Journal article

BACE1 Inhibition Induces a Specific Cerebrospinal Fluid beta-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



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 inhibitio..

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Funding Acknowledgements

The study was supported by the Lundbeck Foundation, the Swedish Research Council, Swedish State Support for Clinical Research, Stiftelsen Psykiatriska Forskningsfonden, Swiss National Science Foundation, Velux Stiftung, Novartis Research Foundation grant, the Soderberg Foundation Stiftelsen Gamla Tjanarinnor, Magn. Bergvalls Stiftelse, Gun och Bertil Stohnes Stiftelse, Uppsala Universitets Medicinska Fakultet Stiftelse for Psykiatrisk och Neurologisk Forskning, the Swedish Brain Fund, the Alzheimer Foundation, Sweden and the Dementia Association, Sweden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.