BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System
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 pre...
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| Format: | Online |
| Language: | English |
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Public Library of Science
2012
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273469/ |
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pubmed-3273469 |
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pubmed-32734692012-02-10 BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System Mattsson, Niklas Rajendran, Lawrence Zetterberg, Henrik Gustavsson, Mikael Andreasson, Ulf Olsson, Maria Brinkmalm, Gunnar Lundkvist, Johan Jacobson, Laura H. Perrot, Ludovic Neumann, Ulf Borghys, Herman Mercken, Marc Dhuyvetter, Deborah Jeppsson, Fredrik Blennow, Kaj Portelius, Erik Research Article 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. Public Library of Science 2012-02-06 /pmc/articles/PMC3273469/ /pubmed/22328928 http://dx.doi.org/10.1371/journal.pone.0031084 Text en Mattsson et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Mattsson, Niklas Rajendran, Lawrence Zetterberg, Henrik Gustavsson, Mikael Andreasson, Ulf Olsson, Maria Brinkmalm, Gunnar Lundkvist, Johan Jacobson, Laura H. Perrot, Ludovic Neumann, Ulf Borghys, Herman Mercken, Marc Dhuyvetter, Deborah Jeppsson, Fredrik Blennow, Kaj Portelius, Erik |
| spellingShingle |
Mattsson, Niklas Rajendran, Lawrence Zetterberg, Henrik Gustavsson, Mikael Andreasson, Ulf Olsson, Maria Brinkmalm, Gunnar Lundkvist, Johan Jacobson, Laura H. Perrot, Ludovic Neumann, Ulf Borghys, Herman Mercken, Marc Dhuyvetter, Deborah Jeppsson, Fredrik Blennow, Kaj Portelius, Erik BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System |
| author_facet |
Mattsson, Niklas Rajendran, Lawrence Zetterberg, Henrik Gustavsson, Mikael Andreasson, Ulf Olsson, Maria Brinkmalm, Gunnar Lundkvist, Johan Jacobson, Laura H. Perrot, Ludovic Neumann, Ulf Borghys, Herman Mercken, Marc Dhuyvetter, Deborah Jeppsson, Fredrik Blennow, Kaj Portelius, Erik |
| author_sort |
Mattsson, Niklas |
| title |
BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System |
| title_short |
BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System |
| title_full |
BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System |
| title_fullStr |
BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System |
| title_full_unstemmed |
BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System |
| title_sort |
bace1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system |
| description |
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. |
| publisher |
Public Library of Science |
| publishDate |
2012 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273469/ |
| _version_ |
1611504152776540160 |