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The acyl-coenzyme A: cholesterol acyltransferase inhibitor CI-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice


Year of Publication:
Contact PI Name:
Dora T. Kovacs
Contact PI Affiliation:
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
Henri J. Huttunen, Daniel Havas, Camilla Peach, Cory Barren, Stephan Duller, Weiming Xia, Matthew P. Frosch, Birgit Hutter-Paier, Manfred Windisch
Primary Reference (PubMED ID):
Funding Source:
National Institute of Neurological Disorders and Stroke (NINDS)
Study Goal and Principal Findings:

Genetic, epidemiological and biochemical studies have suggested that cholesterol is an important risk factor for AD. In previous studies the authors showed that pharmacological or genetic inhibition of acyl-coenzyme A-cholesterol acyltransferase (ACAT), an enzyme that controls cellular equilibrium between free cholesterol and cholesteryl esters, modulates proteolytic processing of APP in vitro and treatment of a Tg mouse model of AD with the ACAT inhibitor CP-113,818 markedly reduced Aβ generation and amyloid pathology, resulting in reversal of cognitive deficits. In this study the authors aimed to test the efficacy of the ACAT inhibitor CI-1011, also known as avasimibe, in transgenic hAPP mouse model of AD. Avasimibe  failed to show significant beneficial effects on coronary atherosclerosis in a recent Ph III trial. In this study the authors tested the anti-amyloidogenic effects of CI-1011 in 2 age groups of hAPP transgenic mice. Data show that CI-1011 partially protected against the development of amyloid pathology in young mice and reduced amyloid burden in old animals with preexisting amyloid deposits. The observed reduction in diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in hAPP mice by limiting generation and increasing clearance of diffusible Aβ.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
C57BL/6 F3

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Load
Dense-core/Compact Plaques
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Liver-Cholesterol Esters
Brain-Cholesterol Esters
CSF-beta Amyloid Peptide 40
CSF-beta Amyloid Peptide 42
Amyloid Precursor Protein (APP) Metabolites
Apolipoprotein E (ApoE)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Acyl-Coenzyme A-Cholesterol Acyltransferase (ACAT)
Presenilin 1 (PS1)
Serum-Total Cholesterol
ATP Binding Cassette Subfamily A Member 1 (ABCA1)
Activated Astrocytes
Activated Microglia
CSF-beta Amyloid Peptide 40
CSF-beta Amyloid Peptide 42
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Target Engagement (Reduction Cholesteryl Ester-Brain)