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University of British Columbia Hospital

Cheryl Wellington, PhD | BC, Canada

University of British Columbia Hospital

Cheryl Wellington, PhD | BC, Canada

Novel modulators of apoE function

Alzheimer's Disease (AD) is the leading cause of dementia in the elderly and causes an enormous financial and emotional burden on patients and their families. Apolipoprotein E (apoE) is a leading risk factor for AD and serves to distribute fats among various cells types in the brain. Our research in mice has shown that the amount of cholesterol (a type of fat) carried on apoE determines how much Aβ, a neuropathological hallmark of AD, is deposited in the brain. We have also discovered that apoE receives fats from the cholesterol transporter ABCA1 and that increasing ABCA1 function promotes apoE-mediated fat transport, facilitates Aβ removal and restores memory in AD mice. Although molecules known as LXR agonists increase ABCA1 and apoE function and effectively cure AD in animal models, they are not safe for use in humans because they unavoidably lead to fatty liver as a harmful side effect. Our objective is to identify new molecules that increase apoE and/or ABCA1 expression without the potential to cause fatty liver. Such compounds may effectively prevent or treat AD. With previous ADDF support, we recently identified 5 molecules, two of which satisfy our criteria for low fatty liver potential. We have also screened 50% of a proprietary natural products library and identified 11 molecules from 100,000 screened that promote apoE expression. In this follow-on study, we will complete screening of the remaining 50% of the natural products library, generate potential drugs from the hits identified thus far using medicinal chemistry, understand how these molecules act to promote apoE expression, and define how we can safely deliver these molecules to mice. Our study has the potential to provide at least one molecule that, in future studies, will be evaluated for its ability to reduce neuropathology and restore memory in AD mice.