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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2012
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oai:doaj.org-article:820b53e8ca3c4c7fb2421581da40bd312021-11-18T07:28:49ZBACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system.1932-620310.1371/journal.pone.0031084https://doaj.org/article/820b53e8ca3c4c7fb2421581da40bd312012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22328928/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203BACE1 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.Niklas MattssonLawrence RajendranHenrik ZetterbergMikael GustavssonUlf AndreassonMaria OlssonGunnar BrinkmalmJohan LundkvistLaura H JacobsonLudovic PerrotUlf NeumannHerman BorghysMarc MerckenDeborah DhuyvetterFredrik JeppssonKaj BlennowErik PorteliusPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e31084 (2012) |
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DOAJ |
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DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
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Medicine R Science Q 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 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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Niklas Mattsson |
| 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. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/820b53e8ca3c4c7fb2421581da40bd31 |
| work_keys_str_mv |
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