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

被引:60
作者
Cook, Jacquelynn J. [3 ]
Wildsmith, Kristin R. [1 ]
Gilberto, David B. [4 ]
Holahan, Marie A. [3 ]
Kinney, Gene G. [5 ]
Mathers, Parker D. [4 ]
Michener, Maria S. [3 ]
Price, Eric A. [5 ]
Shearman, Mark S. [5 ]
Simon, Adam J. [5 ]
Wang, Jennifer X. [2 ]
Wu, Guoxin [5 ]
Yarasheski, Kevin E. [2 ]
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, Dept Imaging, West Point, PA 19486 USA
[4] Merck Res Labs, Dept Lab Anim Resources, West Point, PA 19486 USA
[5] Merck Res Labs, Dept Neurosci, West Point, PA 19486 USA
基金
美国国家卫生研究院;
关键词
ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; MASS-SPECTROMETRY; IN-VITRO; MODULATION; HYPOTHESIS; BIOMARKER; MONKEYS; PLAQUES; PLASMA;
D O I
10.1523/JNEUROSCI.1381-10.2010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The accumulation of amyloid beta (A beta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble A beta species and extracellular plaque formation in the brain. Multiple A beta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of A beta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human A beta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce A beta (beta- and gamma-secretase) is that precursors of A beta may accumulate and cause a rapid increase in A beta production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable-isotope-labeling, and dose-dependently reduced newly generated CNS A beta. In contrast to systemic A beta metabolism, CNS A beta production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than A beta, including C-terminal truncated forms of A beta : 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during gamma-secretase inhibition.
引用
收藏
页码:6743 / 6750
页数:8
相关论文
共 35 条
[21]   First Demonstration of Cerebrospinal Fluid and Plasma Aβ Lowering with Oral Administration of a β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor in Nonhuman Primates [J].
Sankaranarayanan, Sethu ;
Holahan, Marie A. ;
Colussi, Dennis ;
Crouthamel, Ming-Chih ;
Devanarayan, Viswanath ;
Ellis, Joan ;
Espeseth, Amy ;
Gates, Adam T. ;
Graham, Samuel L. ;
Gregro, Allison R. ;
Hazuda, Daria ;
Hochman, Jerome H. ;
Holloway, Katharine ;
Jin, Lixia ;
Kahana, Jason ;
Lai, Ming-tain ;
Lineberger, Janet ;
McGaughey, Georgia ;
Moore, Keith P. ;
Nantermet, Philippe ;
Pietrak, Beth ;
Price, Eric A. ;
Rajapakse, Hemaka ;
Stauffer, Shaun ;
Steinbeiser, Melissa A. ;
Seabrook, Guy ;
Selnick, Harold G. ;
Shi, Xiao-Ping ;
Stanton, Matthew G. ;
Swestock, John ;
Tugusheva, Katherine ;
Tyler, Keala X. ;
Vacca, Joseph P. ;
Wong, Jacky ;
Wu, Guoxin ;
Xu, Min ;
Cook, Jacquelynn J. ;
Simon, Adam J. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2009, 328 (01) :131-140
[22]   Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor [J].
Searfoss, GH ;
Jordan, WH ;
Calligaro, DO ;
Galbreath, EJ ;
Schirtzinger, LM ;
Berridge, BR ;
Gao, H ;
Higgins, MA ;
May, PC ;
Ryan, TP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (46) :46107-46116
[23]   Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers [J].
Siemers, E ;
Skinner, M ;
Dean, RA ;
Gonzales, C ;
Satterwhite, J ;
Farlow, M ;
Ness, D ;
May, PC .
CLINICAL NEUROPHARMACOLOGY, 2005, 28 (03) :126-132
[24]   Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease [J].
Siemers, ER ;
Quinn, JF ;
Kaye, J ;
Farlow, MR ;
Porsteinsson, A ;
Tariot, P ;
Zoulnouni, P ;
Galvin, JE ;
Holtzman, DM ;
Knopman, DS ;
Satterwhite, J ;
Gonzales, C ;
Dean, RA ;
May, PC .
NEUROLOGY, 2006, 66 (04) :602-604
[25]   Direct regulation of intestinal fate by Notch [J].
Stanger, BZ ;
Datar, R ;
Murtaugh, LC ;
Melton, DA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (35) :12443-12448
[26]   Intramembrane Proteolysis by γ-Secretase [J].
Steiner, Harald ;
Fluhrer, Regina ;
Haass, Christian .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (44) :29627-29631
[27]   SENILE PLAQUES IN CORTEX OF AGED NORMAL MONKEYS [J].
STRUBLE, RG ;
PRICE, DL ;
CORK, LC ;
PRICE, DL .
BRAIN RESEARCH, 1985, 361 (1-2) :267-275
[29]   BACE1 -: The β-secretase enzyme in Alzheimer's disease [J].
Vassar, R .
JOURNAL OF MOLECULAR NEUROSCIENCE, 2004, 23 (1-2) :105-113
[30]   Inhibition and modulation of γ-secretase for Alzheimer's disease [J].
Wolfe, Michael S. .
NEUROTHERAPEUTICS, 2008, 5 (03) :391-398