title: BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system.
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.
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden. niklas.mattsson@neuro.gu.se
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rajendran
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Mikael
authors.initials: M
authors.lastname: Gustavsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.forename: Maria
authors.initials: M
authors.lastname: Olsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brinkmalm
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.forename: Ludovic
authors.initials: L
authors.lastname: Perrot
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Herman
authors.initials: H
authors.lastname: Borghys
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.forename: Deborah
authors.initials: D
authors.lastname: Dhuyvetter
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D002853:Chromatography, Liquid; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007118:Immunoassay; D047468:Immunoprecipitation; D008297:Male; D013058:Mass Spectrometry; D053719:Tandem Mass Spectrometry
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D004121:Dimethyl Sulfoxide