The Acyl-Coenzyme A: Cholesterol Acyltransferase Inhibitor CI-1011 Reverses Diffuse Brain Amyloid Pathology in Aged Amyloid Precursor Protein Transgenic Mice

• Published in: Journal of neuropathology and experimental neurology 2010-08, Vol.69 (8), p.777-788
• Main Authors: Huttunen, Henri J, Havas, Daniel, Peach, Camilla, Barren, Cory, Duller, Stephan, Xia, Weiming, Frosch, Matthew P, Hutter-Paier, Birgit, Windisch, Manfred, Kovacs, Dora M
• Format: Article
• Language: English
• Subjects: Acetamides; Acetates - pharmacology; Acetates - therapeutic use; Aging - drug effects; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Animals; Apolipoproteins E - metabolism; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cholesterol - metabolism; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Enzyme-Linked Immunosorbent Assay - methods; Gliosis - drug therapy; Gliosis - etiology; Human viral diseases; Humans; Image Processing, Computer-Assisted; Infectious diseases; Liver - drug effects; Liver - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Neurology; Peptide Fragments - metabolism; Presenilin-1 - metabolism; Pyridines - pharmacology; Sterol O-Acyltransferase - antagonists & inhibitors; Sterol O-Acyltransferase - metabolism; Sulfonamides; Sulfonic Acids - pharmacology; Sulfonic Acids - therapeutic use; Viral diseases; Viral diseases of the nervous system
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e3181e77ed9

Cerebral accumulation of amyloid-β (Aβ) is characteristic of Alzheimer disease and of amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy of CI-1011, an inhibitor of acyl-coenzyme A:cholesterol acyltransferase, which is suitable for clinical use, in reducing amyloid pathology in both young (6.5 months old) and aged (16 months old) human APP transgenic mice. Treatment of young animals with CI-1011 decreased amyloid plaque load in the cortex and hippocampus and reduced the levels of insoluble Aβ40 and Aβ42 and C-terminal fragments of APP in brain extracts. In aged mice, CI-1011 specifically reduced diffuse amyloid plaques with a minor effect on thioflavin S-positive dense-core plaques. Reduced diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in human APP mice by limiting generation and increasing clearance of diffusible Aβ.