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

被引:58
作者
Mattsson, Niklas [1 ]
Rajendran, Lawrence [2 ]
Zetterberg, Henrik [1 ]
Gustavsson, Mikael [1 ]
Andreasson, Ulf [1 ]
Olsson, Maria [1 ]
Brinkmalm, Gunnar [1 ]
Lundkvist, Johan [3 ]
Jacobson, Laura H. [4 ]
Perrot, Ludovic [4 ]
Neumann, Ulf [4 ]
Borghys, Herman [5 ]
Mercken, Marc [5 ]
Dhuyvetter, Deborah [5 ]
Jeppsson, Fredrik [3 ]
Blennow, Kaj [1 ]
Portelius, Erik [1 ]
机构
[1] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Clin Neurochem Lab,Dept Psychiat & Neurochem, Molndal, Sweden
[2] Univ Zurich, Div Psychiat Res, Zurich, Switzerland
[3] AstraZeneca R&D, Innovat Med, Cent Nervous Syst & Pain iMed, Dept Neurosci, Sodertalje, Sweden
[4] Novartis Inst BioMed Res, Basel, Switzerland
[5] Janssen Res & Dev, Neurosci Therapeut Area, Beerse, Belgium
来源
PLOS ONE | 2012年 / 7卷 / 02期
基金
瑞士国家科学基金会;
关键词
PROTEIN-CLEAVING ENZYME; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; SECRETASE ACTIVITY; PEPTIDE; EXPRESSION; CLEAVAGE; BRAIN; PURIFICATION; GENERATION;
D O I
10.1371/journal.pone.0031084
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
BACE1 is a key enzyme for amyloid-beta (A beta) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal A beta metabolism, inducing a unique pattern of secreted Ab 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 A beta 1-40 and A beta 1-42, treatment also changed the relative levels of several other A beta isoforms. In particular A beta 1-34 decreased, while A beta 5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in A beta 1-40 and A beta 1-42. The effects on A beta 5-40 indicate the presence of a BACE1 independent pathway of APP degradation. The described CSF A beta 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.
引用
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页数:11
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