BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System

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

doi:10.1371/journal.pone.0031084

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Peer-reviewed

Research Article

BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System

Niklas Mattsson ,

* E-mail: niklas.mattsson@neuro.gu.se (NM); erik.portelius@neuro.gu.se (EP)

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
Lawrence Rajendran,

Affiliation Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, University of Zurich, Zurich, Switzerland
⨯
Henrik Zetterberg,

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
Mikael Gustavsson,

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
Ulf Andreasson,

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
Maria Olsson,

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
Gunnar Brinkmalm,

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
Johan Lundkvist,

Affiliation Innovative Medicines, Central Nervous System and Pain iMed, Department of Neuroscience, AstraZeneca R&D, Södertälje, Sweden
⨯
Laura H. Jacobson,

Affiliation Neuroscience Discovery, Novartis Institutes for BioMedical Research, Basel, Switzerland
⨯
Ludovic Perrot,

Affiliation Neuroscience Discovery, Novartis Institutes for BioMedical Research, Basel, Switzerland
⨯
Ulf Neumann,

Affiliation Neuroscience Discovery, Novartis Institutes for BioMedical Research, Basel, Switzerland
⨯
Herman Borghys,

Affiliation Neuroscience Therapeutic Area, Janssen Research and Development, Beerse, Belgium
⨯
Marc Mercken,

Affiliation Neuroscience Therapeutic Area, Janssen Research and Development, Beerse, Belgium
⨯
Deborah Dhuyvetter,

Affiliation Neuroscience Therapeutic Area, Janssen Research and Development, Beerse, Belgium
⨯
Fredrik Jeppsson,

Affiliation Innovative Medicines, Central Nervous System and Pain iMed, Department of Neuroscience, AstraZeneca R&D, Södertälje, Sweden
⨯
Kaj Blennow,

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
[ ... ],
Erik Portelius

* E-mail: niklas.mattsson@neuro.gu.se (NM); erik.portelius@neuro.gu.se (EP)

Affiliation Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⨯
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BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System

Niklas Mattsson,
Lawrence Rajendran,
Henrik Zetterberg,
Mikael Gustavsson,
Ulf Andreasson,
Maria Olsson,
Gunnar Brinkmalm,
Johan Lundkvist,
Laura H. Jacobson,
Ludovic Perrot

Published: February 6, 2012
https://doi.org/10.1371/journal.pone.0031084

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Absence of structures

Posted by cdsouthan on 23 Dec 2012 at 12:13 GMT

Considering the profile of this journal with respect to transparency, the omission of the explicit inhibitor chemical structures is unexpected. Without them the key experiments in the paper cannot be reproduced

No competing interests declared.

RE: Absence of structures

eportan replied to cdsouthan on 04 Feb 2013 at 11:46 GMT

Novartis is willing to provide the inhibitor they supplied for this study under a Material Transfer Agreement for academic research and non-commercial purposes. Please contact Ulf Neumann (ulf.neumann@novartis.com).

Compound S is identical to compound J in the published BACE2/diabetes Cell metabolism paper:
Cell Metabolism, Volume 14, issue 3, 7 september 2011, Pages 365-377. This reference describes the synthesis in more detail:

2-Aminodihydro[1,3]thiazines as BACE 2 inhibitors and their preparation and use in the treatment of diabetes.
Beauchamp, Jeremy; Benardeau, Agnes; Hilpert, Hans; Migliorini, Cristiano; Riboulet, William; Wang, Haiyan
PCT Int. Appl. (2011), WO 2011029803 A1’

No competing interests declared.

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BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System

BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System

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Absence of structures

Posted by cdsouthan on 23 Dec 2012 at 12:13 GMT

RE: Absence of structures

eportan replied to cdsouthan on 04 Feb 2013 at 11:46 GMT