The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease

被引:217
作者
Hutter-Paier, B
Huttunen, HJ
Puglielli, L
Eckman, CB
Kim, DY
Hofmeister, A
Moir, RD
Domnitz, SB
Frosch, MP
Windisch, M
Kovacs, DM [1 ]
机构
[1] Harvard Univ, Sch Med, Neurobiol Dis Lab, Charlestown, MA 02129 USA
[2] Harvard Univ, Sch Med, Genet & Aging Res Unit, Charlestown, MA 02129 USA
[3] Harvard Univ, Sch Med, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA
[4] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Charlestown, MA 02129 USA
[5] Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA
[6] JSW Res Forsch Labor GmbH, Inst Expt Pharmacol, A-8020 Graz, Austria
关键词
D O I
10.1016/j.neuron.2004.08.043
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Amyloid beta-peptide (Abeta) accumulation in specific brain regions is a pathological hallmark of Alzheimer's disease (AD). We have previously reported that a well characterized acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, inhibits Abeta production in cell-based experiments. Here, we assessed the efficacy of CP-113,818 in reducing AD-like pathology in the brains of transgenic mice expressing human APP(751) containing the London (V7171) and Swedish (K670M/N671L) mutations. Two months of treatment with CP-113,818 reduced the accumulation of amyloid plaques by 88%-99% and membrane/insoluble Abeta levels by 83%-96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Abeta(42) was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Abeta levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain. Our results suggest that ACAT inhibition may be effective in the prevention and treatment of AD by inhibiting generation of the Abeta peptide.
引用
收藏
页码:227 / 238
页数:12
相关论文
共 45 条
[1]   Games played by rogue proteins in prion disorders and Alzheimer's disease [J].
Aguzzi, A ;
Haass, C .
SCIENCE, 2003, 302 (5646) :814-818
[2]   Familial Alzheimer's disease-linked presenilin 1 variants elevate A beta 1-42/1-40 ratio in vitro and in vivo [J].
Borchelt, DR ;
Thinakaran, G ;
Eckman, CB ;
Lee, MK ;
Davenport, F ;
Ratovitsky, T ;
Prada, CM ;
Kim, G ;
Seekins, S ;
Yager, D ;
Slunt, HH ;
Wang, R ;
Seeger, M ;
Levey, AI ;
Gandy, SE ;
Copeland, NG ;
Jenkins, NA ;
Price, DL ;
Younkin, SG .
NEURON, 1996, 17 (05) :1005-1013
[3]   A novel proteolytic cleavage involved in Notch signaling:: The role of the disintegrin-metalloprotease TACE [J].
Brou, C ;
Logeat, F ;
Gupta, N ;
Bessia, C ;
LeBail, O ;
Doedens, JR ;
Cumano, A ;
Roux, P ;
Black, RA ;
Israël, A .
MOLECULAR CELL, 2000, 5 (02) :207-216
[4]   Cholesterol in Alzheimer's disease and tauopathy [J].
Burns, M ;
Duff, K .
ALZHEIMER'S DISEASE: VASCULAR ETIOLOGY AND PATHOLOGY, 2002, 977 :367-375
[5]   RAPID INDUCTION OF ALZHEIMER A-BETA AMYLOID FORMATION BY ZINC [J].
BUSH, AI ;
PETTINGELL, WH ;
MULTHAUP, G ;
PARADIS, MD ;
VONSATTEL, JP ;
GUSELLA, JF ;
BEYREUTHER, K ;
MASTERS, CL ;
TANZI, RE .
SCIENCE, 1994, 265 (5177) :1464-1467
[6]   Augmented senile plaque load in aged female β-amyloid precursor protein-transgenic mice [J].
Callahan, MJ ;
Lipinski, WJ ;
Bian, F ;
Durham, RA ;
Pack, A ;
Walker, LC .
AMERICAN JOURNAL OF PATHOLOGY, 2001, 158 (03) :1173-1177
[7]   The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: Implications for Alzheimer's disease [J].
Champagne, D ;
Pearson, D ;
Dea, D ;
Rochford, J ;
Poirier, J .
NEUROSCIENCE, 2003, 121 (01) :99-110
[8]  
Chang CCY, 2000, J BIOL CHEM, V275, P28083
[9]  
Chang TY, 2001, J LIPID RES, V42, P1933
[10]   Alzheimer's disease: treatments in discovery and development [J].
Citron, M .
NATURE NEUROSCIENCE, 2002, 5 (Suppl 11) :1055-1057