UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Mattsson, N; Rajendran, L; Zetterberg, H; Gustavsson, M; Andreasson, U; Olsson, M; Brinkmalm, G; ... Portelius, E; + view all (2012) BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system. PLoS One , 7 (2) , Article e31084. 10.1371/journal.pone.0031084. Green open access

[thumbnail of journal.pone.0031084.pdf]
Preview
PDF
journal.pone.0031084.pdf

Download (1MB)

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.

Type: Article
Title: BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0031084
Publisher version: http://dx.doi.org/10.1371/journal.pone.0031084
Language: English
Additional information: © 2012 Mattsson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3273469
Keywords: Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Aspartic Acid Endopeptidases, Cell Line, Central Nervous System, Cerebrospinal Fluid, Chromatography, Liquid, Dimethyl Sulfoxide, Dogs, Enzyme Inhibitors, Female, Humans, Immunoassay, Immunoprecipitation, Male, Mass Spectrometry, Tandem Mass Spectrometry
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1411983
Downloads since deposit
125Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item