The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease.
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 (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 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.
JSW-Research Forschungslabor GmbH, Institute of Experimental Pharmacology, Rankengasse 28, 8020 Graz, Austria.
Birgit
B
Hutter-Paier
Henri J
HJ
Huttunen
Luigi
L
Puglielli
Christopher B
CB
Eckman
Doo Yeon
DY
Kim
Alexander
A
Hofmeister
Robert D
RD
Moir
Sarah B
SB
Domnitz
Matthew P
MP
Frosch
Manfred
M
Windisch
Dora M
DM
Kovacs
D000311:Adrenal Glands / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002788:Cholesterol Esters / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D012737:Sex Factors; D002785:Sterol O-Acyltransferase / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D011725:Pyridines; C087132:CP 113818; D002785:Sterol O-Acyltransferase