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2016 Grants - Pasquale
Inhibiting the EphA4 Receptor to Counteract Alzheimer’s Neurodegeneration
Elena Pasquale, Ph.D.
Sanford-Burnham Medical Research Institute
La Jolla, California
2016 Collaboration 4 Cure (C4C)
Can novel drug-like molecules stop abnormal clumps of the beta-amyloid protein from blocking nerve cell repair in people with Alzheimer’s disease?
The EphA4 receptor is a protein that acts as a “docking site” on nerve cells. Certain molecules and proteins can bind to EphA4 at specific sites located both inside and outside of the nerve cell. Small abnormal clumps of beta-amyloid protein fragments, called oligomers, are commonly found in the brains of individuals with Alzheimer’s disease and can bind to EphA4, over activating the receptor. This over activation may block nerve cell repair mechanisms and trigger nerve cell destruction, contributing to Alzheimer’s disease progression.
Blocking the sites on EphA4 where the beta-amyloid oligomers attach may promote nerve cell repair. However these sites on the outside of the cell have proven difficult to target. Researchers hypothesize that blocking activity of the EphA4 receptor from inside the cell may be more effective at halting the negative effects of beta-amyloid oligomers. However, it is critical that any molecule used for therapeutics is very specific for EphA4 and does not bind to other similar proteins in and around the nerve cell. This type of “non-specific” binding can lead to unwanted side effects.
Elena Pasquale, Ph.D. and colleagues plan to perform a series of experiments to identify drug-like molecules which specifically bind to EphA4 inside nerve cells. Using nerve cells grown in laboratory dishes, the researchers will screen large chemical libraries for compounds that can block EphA4 activity. Molecules which are found to turn off EphA4 activity, particularly in the presence of beta-amyloid oligomers, will be selected for further study in Alzheimer’s-like mice. These identified drug candidates will be assessed to determine whether or not they activate other proteins found in the nerve cell membrane which could lead to unwanted side effects.
This study may identify drug candidates that could counteract the negative effects of beta-amyloid oligomers on nerve cells in individuals with Alzheimer’s disease. This will be the first time researchers have targeted EphA4 specifically inside nerve cells; novel compounds that target this pathway could serve as the basis for new candidates for drug development.