2022 Alzheimer's Association Research Grant (AARG)
A Drug Screening Assay to Reduce LINGO-1 Amounts in Neurons
Can a novel test monitor the effectiveness of a potential drug for Alzheimer’s?
Brian Chen, Ph.D.
McGill University Health Centre
Montreal, Canada
Background
According to recent studies, a protein called leucine rich repeat and immunoglobin-like domain-containing protein 1 (LINGO-1) may contribute to the development of Alzheimer’s. This protein has been linked to molecular mechanisms that lead to the death of nerve cells and prevent the development of new nerve cells. LINGO-1 has also been linked to the production of beta-amyloid, a protein fragment that accumulates into hallmark plaques in the Alzheimer’s brain. Because of these findings, researchers have been working to produce drug compounds that target LINGO-1 and slow Alzheimer’s progression.
The process of making drugs that target LINGO-1 has been challenging because it involves specific tests that measure how well a drug can reduce LINGO-1 levels in nerve cells. Dr. Brian Chen and colleagues have developed such a test, which they call the Protein Quantitation Rationing (PQR) screening platform. This drug compound screening platform works by inserting specific genetic information into the gene for a target protein, for this study, LINGO-1. Then, when the gene is made into the protein, the process also creates a fluorescent molecule that is attached to the protein and can “highlight” it under a microscope. The researchers can then monitor the activity of that protein in a nerve cell, and they can determine how levels of the protein may change over time after the nerve cell is exposed to a drug compound.
Research Plan
For their research grant, Dr. Chen and team will examine how well PQR can identify drugs that effectively target LINGO-1. First, the researchers will administer their drug test on cells grown in the laboratory called human “neural precursor cells” (immature cells with the ability to develop into nerve cells) that have LINGO-1. They will then study how well the fluorescent molecules work to visualize and monitor changes in LINGO-1 levels over time. After exposing the cells to large numbers of potential drugs, they will use the PQR test to determine how well these compounds can eliminate LINGO-1. Finally, the investigators will examine whether PQR can be safely and effectively administered in living mice.
Impact
If successful, the results from this project could lead to future studies that assess drugs that target LINGO-1 in living mice and human brains. Ultimately, such work could identify a novel drug therapy for Alzheimer’s.