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

Artikel i vetenskaplig tidskrift
Författare Niklas Mattsson
Lawrence Rajendran
Henrik Zetterberg
Mikael K 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
Publicerad i PloS one
Volym 7
Nummer/häfte 2
Sidor e31084
ISSN 1932-6203
Publiceringsår 2012
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor e31084
Språk en
Länkar dx.doi.org/10.1371/journal.pone.003...
Ämnesord Amyloid Precursor Protein Secretases, antagonists & inhibitors, Amyloid beta-Peptides, metabolism, Amyloid beta-Protein Precursor, metabolism, Animals, Aspartic Acid Endopeptidases, antagonists & inhibitors, Cell Line, Central Nervous System, drug effects, metabolism, Cerebrospinal Fluid, metabolism, Chromatography, Liquid, Dimethyl Sulfoxide, pharmacology, Dogs, Enzyme Inhibitors, pharmacology, Female, Humans, Immunoassay, Immunoprecipitation, Male, Mass Spectrometry, Tandem Mass Spectrometry
Ämneskategorier Neurologi, Neurokemi

Sammanfattning

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.

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