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

• Published in: Neuron (Cambridge, Mass.) Vol. 44; no. 2; pp. 227 - 238
• Main Authors: Hutter-Paier, Birgit, Huttunen, Henri J., Puglielli, Luigi, Eckman, Christopher B., Kim, Doo Yeon, Hofmeister, Alexander, Moir, Robert D., Domnitz, Sarah B., Frosch, Matthew P., Windisch, Manfred, Kovacs, Dora M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.10.2004; Elsevier Limited
• Subjects: Adrenal Glands - drug effects; Alzheimer Disease - drug therapy; Alzheimer Disease - prevention & control; Alzheimer's disease; Amyloid beta-Peptides - drug effects; Amyloid beta-Peptides - metabolism; Animal cognition; Animals; Blotting, Western; Brain - drug effects; Brain - pathology; Brain research; Cell culture; Cholesterol; Cholesterol Esters - analysis; Cholesterol Esters - metabolism; Disease Models, Animal; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - therapeutic use; Enzymes; Female; Homeostasis; Humans; Learning - drug effects; Male; Mice; Mice, Transgenic; Pathology; Plaque, Amyloid - metabolism; Pyridines - adverse effects; Pyridines - therapeutic use; Sex Factors; Statins; Sterol O-Acyltransferase - drug effects; Sterol O-Acyltransferase - metabolism; Studies
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2004.08.043

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 APP 751 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 Aβ 42 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.