Current drugs used to treat Alzheimer’s disease (AD) ameliorate the symptoms of the disease but do not slow or reverse disease progression. Part of the reason for this has been a lack of knowledge on specific and actionable biological molecules that contribute to the disease and that can be targeted with drugs. In recent years, several large genomics studies of tens of thousands of patients with AD have provided new insights into the causes of the disease, leading to several new potential targets for drug treatment. One of the most promising targets to arise from these studies is Phospholipase C-gamma-2, abbreviated as PLC-gamma-2. A natural variant of PLC-gamma-2 harboring a single substitution (P522R) of one residue out of more than 1,200 that make up the protein provides protection from Alzheimer’s disease. Protection is robust, reproducible and, perhaps most promising of all, patients with mild cognitive impairment that express PLC-gamma-2 (P522R) show slower cognitive decline relative to noncarriers.
PLC-gamma-2 (P522R) is more active than its more frequent, wild-type counterpart, and it generally is accepted that protection from AD arises from this increased activity. We intend to recapitulate this increased activity for wild-type PLC-gamma-2 using small molecules. We have developed a high-throughput screen that allows us to search a large collection of small molecules for activators of PLC-gamma-2. We will carry out this screen for more than 100,000 compounds and optimize compounds that activate PLC-gamma-2. These optimized compounds will serve as the initial leads for further work to develop drugs to treat Alzheimer’s disease.