Neuron
Volume 44, Issue 2, 14 October 2004, Pages 227-238
Journal home page for Neuron

Article
The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease

https://doi.org/10.1016/j.neuron.2004.08.043Get rights and content
Under an Elsevier user license
open archive

Abstract

Amyloid β-peptide (Aβ) 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 Aβ 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 APP751 containing the London (V717I) 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 Aβ levels by 83%–96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Aβ42 was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Aβ 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 Aβ peptide.

Cited by (0)

7

These authors contributed equally to this work.

8

Present address: Department of Medicine, Section of Geriatrics and Gerontology, University of Wisconsin-Madison, Veterans Administration Hospital (GRECC 11G), 2500 Overlook Terrace, Madison, Wisconsin 53705.