Optimization of Novel ACAT Inhibitors for Alzheimer’s Disease

The goal of this project is to test three novel ACAT inhibitors to determine whether they will prevent development of amyloid pathology and alter APP processing in AD mice in order to prevent and treat AD.

High cholesterol is associated with cardiovascular disease and also regulates the production of the toxic Abeta peptide in Alzheimer’s disease (AD). Professor Kovacs previously found that drugs specifically targeting an enzyme of the cholesterol pathway, acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors reduce generation of the toxic Abeta peptides in cells and animal models of AD. Most importantly, she and her team recently used a potentially clinically relevant ACAT inhibitor, CI-1011, in aged mice after abundant amyloid deposition. CI-1011 has previously reached phase III clinical trials for prevention of atherosclerosis (but was later discontinued). In aged mice, CI-1011 dramatically decreased diffuse amyloid, which is most toxic for neuronal function (Huttunen, 2010).

Their data show that ACAT inhibition can reverse existing amyloid pathology, not just prevent novel pathology from forming. ACAT inhibitors are not yet marketed against cardiovascular disease. Dr. Kovacs and associates have recently designed and screened a library of 45 novel ACAT inhibitors, based on the structure of CI-1011. From this screen, they identified three novel ACAT inhibitors that reduce Abeta generation. They will optimize these three inhibitors by screening a novel library of compounds based on their structure and determine whether the novel inhibitors prevent development of amyloid pathology and alter APP processing in AD mice in absence of toxicity. These studies should result in one or more novel ACAT inhibitor with the potential to prevent and treat AD.