The Acyl-coenzyme a: Cholesterol acyltransferase inhibitor ci-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice

Henri J. Huttunen, Daniel Havas, Camilla Peach, Cory Barren, Stephan Duller, Weiming Xia, Matthew P. Frosch, Birgit Hutter-Paier, Manfred Windisch, Dora M. Kovacs

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)777-788
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume69
Issue number8
DOIs
StatePublished - Aug 2010

Keywords

  • Alzheimer disease
  • Cholesterol transport
  • Glia
  • Lipids
  • Neurodegeneration
  • Transgenic.

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

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