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

页数：11

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