Targeted Discovery of LR11/SorLA-Based AD Therapeutics

Project Summary

Because of the strong association between aging and Alzheimer's disease, it is becoming an increasingly important public health concern as life expectancies increase and the number of affected individuals grows. Despite rapid growth in our scientific understanding of Alzheimer's disease, current treatments are relatively ineffective. In earlier studies, we discovered a novel association between a receptor called LR11 (also known as SorLA) and Alzheimer's disease. LR11 levels were consistently reduced in the brains of patients with AD compared to normal individuals. Additional research findings indicate that changes in LR11 may occur early in the disease process and that LR11 may play an important role in regulating the levels of amyloid-beta peptide, which is believed to play a central role in causing Alzheimer's disease. The evidence emerging from our study of LR11 suggests that it represents an important new therapeutic target for Alzheimer's disease. We hypothesize that LR11 will be a good target for discovery of candidate compounds that can modulate amyloid-beta through interactions with LR11. We propose to initiate a search for LR11-interacting compounds, which will produce leads in the development of new therapeutic agents. To accomplish this, we will combine our scientific expertise with the capabilities of the NIH-funded Emory Molecular Libraries Screening Center to develop tools to identify and evaluate candidate compounds that interact with LR11. In Aim 1, we will develop high throughput assays to screen a library of small compounds for those capable of interacting with specific portions of LR11. In Aim 2, we will develop cell-based assays to identify relevant LR11-interacting compounds. In Aim 3, we will test the ability of LR11-interacting molecules to modulate amyloid-beta levels to refine the list to the most promising compounds and expedite future efforts to develop LR11-based therapeutic agents. The long-term goal of these studies is to exploit our understanding of LR11 to develop new treatments that can slow or prevent the development of Alzheimer's disease.