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2005 Grants - Lingbeck
LRP-Mediated Intraneuronal Accumulation of Beta-Amyloid
Jody L. Lingbeck, Ph.D.
St. Louis, Missouri
2005 New Investigator Research Grant
Beta-amyloid, a tiny protein fragment, is a key suspect in the pathology of Alzheimer's disease, but the exact way that amyloid is toxic remains unknown. This protein fragment tends to aggregate, or clump together, in the spaces between nerve cells and other cells in the brain. Recently, however, evidence has shown that the protein fragment also aggregates within nerve cells. This finding has changed the way scientists think about its potential toxicity.
Just how beta-amyloid aggregates within nerve cells is unclear. Jody L. Lingbeck, Ph.D., and colleagues hypothesize that uptake of beta-amyloid from outside the cells may be the driving force behind these "intracellular" aggregates inside nerve cells. To test this theory, the scientists will examine the relationship between a protein called LRP, or low-density lipoprotein receptor-related protein, and intracellular beta-amyloid aggregates.
Previously, the investigators found that LRP can increase the amount of beta-amyloid in cells. Now they are going to genetically manipulate mice so that they lack copies of the gene for LRP. They will then inject beta-amyloid into the brains of these animals and determine if uptake of the protein into nerve cells is compromised. They will also determine how another protein, called apolipoprotein E, affects this process. Some forms of apolipoprotein E have been linked to increased risk for developing Alzheimer's disease and the protein is known to bind to LRP. These experiments may help explain why beta-amyloid accumulates within cells and could reveal means to prevent this process.