CNS Amyloid-β, Soluble APP-α and -β Kinetics during BACE Inhibition

被引：37

作者：

Dobrowolska, Justyna A. ^{[1
]}

Michener, Maria S. ^{[5
]}

Wu, Guoxin ^{[3
]}

Patterson, Bruce W. ^{[2
]}

Chott, Robert ^{[2
]}

Ovod, Vitaliy ^{[1
]}

Pyatkivskyy, Yuriy ^{[1
]}

Wildsmith, Kristin R. ^{[1
]}

Kasten, Tom ^{[1
]}

Mathers, Parker ^{[5
]}

Dancho, Mandy ^{[5
]}

Lennox, Christina ^{[5
]}

Smith, Brad E. ^{[5
]}

Gilberto, David ^{[5
]}

McLoughlin, Debra ^{[8
,9
]}

Holder, Daniel J. ^{[7
]}

Stamford, Andrew W. ^{[6
]}

Yarasheski, Kevin E. ^{[2
]}

Kennedy, Matthew E. ^{[4
]}

Savage, Mary J. ^{[3
]}

Bateman, Randall J. ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[3] Merck Res Labs, Mol Biomarkers, West Point, PA 19486 USA

[4] Merck Res Labs, West Point, PA 19486 USA

[5] Merck Res Labs, Safety & Lab Anim Resources, West Point, PA 19486 USA

[6] Merck Res Labs, Med Chem, West Point, PA 19486 USA

[7] Merck Res Labs, Early Dev Stat, West Point, PA 19486 USA

[8] Merck Res Labs, Preclin Drug Metab, West Point, PA 19486 USA

[9] Merck Res Labs, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF NEUROSCIENCE | 2014年 / 34卷 / 24期

基金：

美国国家卫生研究院;

关键词：

amyloid beta; amyloid precursor protein; BACE inhibitor; sAPP alpha; sAPP beta; SILK; PRECURSOR PROTEIN; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; DESIGN; IDENTIFICATION; EXPRESSION; CLEARANCE; TAK-070; POTENT;

D O I：

10.1523/JNEUROSCI.0540-14.2014

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

BACE, a beta-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the beta-secretase pathway and a lowering of CNS amyloid-beta (A beta) levels. The interaction of the beta-secretase and alpha-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated A beta and soluble APP beta (sAPP beta), with increased newly generated sAPP alpha. A stable isotope labeling kinetics experiment in NHPs was performed with a C-13(6)-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPP alpha, sAPP beta, and A beta in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPP alpha, sAPP beta, and A beta were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPP beta and sAPP alpha kinetics were similar, but both significantly slower than A beta. BACE inhibition resulted in decreased labeled sAPP beta and A beta in CSF, without observable changes in labeled CSF sAPP alpha. ELISA concentrations of sAPP beta and A beta both decreased and sAPP alpha increased. sAPP alpha increased by ELISA, with no difference by labeled sAPP alpha kinetics indicating increases in product may be due to APP shunting from the beta-secretase to the alpha-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.

引用

页码：8336 / 8346

页数：11

共 50 条

[1]

Clinical and neurobiological correlates of soluble amyloid precursor proteins in the cerebrospinal fluid [J].

Alexopoulos, Panagiotis ;

Tsolakidou, Amalia ;

Roselli, Francesco ;

Arnold, Anila ;

Grimmer, Timo ;

Westerteicher, Christine ;

Leante, Maria Rosaria ;

Foerstl, Hans ;

Livrea, Paolo ;

Kurz, Alexander ;

Perneczky, Robert .

ALZHEIMERS & DEMENTIA, 2012, 8 (04) :304-311

[2]

Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates [J].

Bateman, Randall J. ;

Munsell, Ling Y. ;

Chen, Xianghong ;

Holtzman, David M. ;

Yarasheski, Kevin E. .

JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY, 2007, 18 (06) :997-1006

[3]

Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo [J].

Bateman, Randall J. ;

Munsell, Ling Y. ;

Morris, John C. ;

Swarm, Robert ;

Yarasheski, Kevin E. ;

Holtzman, David M. .

NATURE MEDICINE, 2006, 12 (07) :856-861

[4]

A γ-Secretase Inhibitor Decreases Amyloid-β Production in the Central Nervous System [J].

Bateman, Randall J. ;

Siemers, Eric R. ;

Mawuenyega, Kwasi G. ;

Wen, Guolin ;

Browning, Karen R. ;

Sigurdson, Wendy C. ;

Yarasheski, Kevin E. ;

Friedrich, Stuart W. ;

DeMattos, Ronald B. ;

May, Patrick C. ;

Paul, Steven M. ;

Holtzman, David M. .

ANNALS OF NEUROLOGY, 2009, 66 (01) :48-54

[5]

Bernier F, 2013, ALZHEIMERS DEMENT, V9, pP886, DOI DOI 10.1016/J.JALZ.2013.08.244

[6]

Soluble amyloid precursor protein α and β in CSF in Alzheimer's disease [J].

Brinkmalm, Gunnar ;

Brinkmalm, Ann ;

Bourgeois, Philippe ;

Persson, Rita ;

Hansson, Oskar ;

Portelius, Erik ;

Mercken, Marc ;

Andreasson, Ulf ;

Parent, Stephane ;

Lipari, Francesco ;

Ohrfelt, Annika ;

Bjerke, Maria ;

Minthon, Lennart ;

Zetterberg, Henrik ;

Blennow, Kaj ;

Nutu, Magdalena .

BRAIN RESEARCH, 2013, 1513 :117-126

[7]

GENERATION OF BETA-AMYLOID IN THE SECRETORY PATHWAY IN NEURONAL AND NONNEURONAL CELLS [J].

BUSCIGLIO, J ;

GABUZDA, DH ;

MATSUDAIRA, P ;

YANKNER, BA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (05) :2092-2096

[8]

Acute γ-Secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid-β Production to Alternative APP Fragments without Amyloid-β Rebound [J].

Cook, Jacquelynn J. ;

Wildsmith, Kristin R. ;

Gilberto, David B. ;

Holahan, Marie A. ;

Kinney, Gene G. ;

Mathers, Parker D. ;

Michener, Maria S. ;

Price, Eric A. ;

Shearman, Mark S. ;

Simon, Adam J. ;

Wang, Jennifer X. ;

Wu, Guoxin ;

Yarasheski, Kevin E. ;

Bateman, Randall J. .

JOURNAL OF NEUROSCIENCE, 2010, 30 (19) :6743-6750

[9]

Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor [J].

Cumming, Jared N. ;

Smith, Elizabeth M. ;

Wang, Lingyan ;

Misiaszek, Jeffrey ;

Durkin, James ;

Pan, Jianping ;

Iserloh, Ulrich ;

Wu, Yusheng ;

Zhu, Zhaoning ;

Strickland, Corey ;

Voigt, Johannes ;

Chen, Xia ;

Kennedy, Matthew E. ;

Kuvelkar, Reshma ;

Hyde, Lynn A. ;

Cox, Kathleen ;

Favreau, Leonard ;

Czarniecki, Michael F. ;

Greenlee, William J. ;

McKittrick, Brian A. ;

Parker, Eric M. ;

Stamford, Andrew W. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (07) :2444-2449

[10]

Mechanism-based pharmacokinetic-pharmacodynamic modeling - A new classification of biomarkers [J].

Danhof, M ;

Alvan, G ;

Dahl, SG ;

Kuhlmann, J ;

Paintaud, G .

PHARMACEUTICAL RESEARCH, 2005, 22 (09) :1432-1437

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