Karen Gylys, Ph.D.
University of Los Angeles
Los Angeles, California

2003 New-Investigator Research Grant

Scientists have so far identified one gene associated with an increased risk of developing late-onset Alzheimer’s, the common form of the disease that tends to appear late in life with no clear inheritance pattern. This risk gene, APOE-e4, is one form of the gene providing the blueprint for apolipoprotein E, a protein that transports cholesterol. Scientists have not yet discovered the molecular mechanisms linking APOE-e4 to Alzheimer pathology.

This project will explore whether APOE-e4 increases production of beta-amyloid, the protein fragment that is the chief component of the amyloid plaques that are a hallmark Alzheimer brain abnormality. A growing number of researchers believe that beta-amyloid does its most serious damage before it is deposited in plaques and that disruption of synapses is one of the fragment’s most damaging effects. Synapses are microscopic gaps between nerve cells where chemical messages travel from one cell to another. Patterns in synaptic connections and the flow of messenger chemicals comprise the brain’s information processing, learning, and memory networks.

The team will use advanced analytic techniques to determine the levels of beta-amyloid and synapse loss in postmortem samples of brain tissue from individuals with Alzheimer’s. The researchers will also compare amyloid and synapse levels in brain tissue samples from mice genetically engineered to express human APOE-e4 as well as APOE-e3, another form of the gene not associated with increased Alzheimer risk. They believe that APOE-e4 samples will show greater levels of beta-amyloid and synapse loss. This project may set the stage for future work to help determine why certain brain cells and not others are especially susceptible to Alzheimer’s disease.