A research led by Dr. Ta-Yuan Chang, a researcher at Dartmouth Medical School, in collaboration with Dr. Nabil G. Seidah, Director of the Research Unit on Biochemical Neuroendocrinology at the IRCM, shows that using specific inhibitors of ACAT1’s expression and activity could be a new and extremely interesting therapeutic option to treat Alzheimer’s disease. This study was published online today in the prestigious journal Proceedings of the National Academy of Sciences of the United States of America (PNAS). Dr. Estelle Rousselet, a post-doctoral fellow in Dr. Seidah’s laboratory, is also listed among the authors.

It has already been established that cholesterol metabolism was implicated in the pathogenesis of several neurodegenerative diseases, such as Alzheimer’s disease. In fact, many studies show that cholesterol has an effect on the accumulation of amyloid beta, which is observed in Alzheimer’s disease, resulting in part from its capacity to modulate the enzymes responsible for its synthesis. The Acyl-CoA:cholesterolacyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to esters. Previous studies have shown that inhibitors of these enzymes decrease significantly the accumulation of amyloid plaques and improve cognitive abilities in mice that developed symptoms of Alzheimer’s disease. The data suggest therefore that ACAT enzymes play a crucial role in the progression of Alzheimer’s disease. However, the specificity of those inhibitors on ACAT enzymes, as well as their mechanism of action underlying this protection remain unknown.

Researchers used transgenic mice that develop Alzheimer’s disease in which the Acat1 gene was knocked out. They were able to show that the isoenzyme ACAT1 is the most common enzyme in mouse brain. In those mice, APP levels, a precursor at the root of amyloid beta production in Alzheimer’s disease, are reduced by more than 60%, thus largely reducing the accumulation of amyloid plaques. The cognitive functions of those mice also increased. Moreover, the authors also defined the underlying biochemical mechanisms. ACAT1, which is mostly localized within the endoplasmic reticulum (ER), decreases the amount of free cholesterol within membranes by transforming it into esterified cholesterol. Without it, the free cholesterol pool in the ER rises and is then transformed into a cholesterol metabolite: 24SOH. This increase in the level of ER 24SOH and/or that of free cholesterol results in a decrease of APP protein production, likely through an accelerated degradation at the level of the ER and would thus decrease amyloid beta formation and amyloid plaques burden.

This study clearly fosters an interest for developing ACAT1 specific inhibitors in order to treat patients suffering from Alzheimer’s disease.

This work was supported by the National Institutes of Health (NIH, for Dr. Chang) and the Canadian Institutes of Health Research (CIHR, for Dr. Seidah).

This article is available online at:
http://www.pnas.org/content/early/recent

Dr. Nabil G. Seidah is Director of the Research Unit on Biochemical Neuroendocrinology and Director of the Cardiovascular and Metabolic Diseases Research Program at the IRCM. He is the leader of a CIHR pan-Canadian team on the role of proteases in cardiovascular disorders. He is also Full Research Professor IRCM, Full Researcher at the department of medicine at the Université de Montréal and Associate Member of the department of experimental medicine at McGill University. Dr. Seidah is the holder of a Canada Research Chair in Precursor Proteolysis.

Communications Department