Bibliographic
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.