Ab and Neurodegeneration

Our work is designed to investigate the role of certain peptides, both alone and in combination, as direct causes of chronic brain cell death. We will accomplish this by using a simplified genetically controlled model organism. We also believe that our preliminary observations indicate a new cellular pathway that may be responsible for Alzheimer’s related cell death. We will thus try and prove this hypothesis using genetic and drug based experimental strategies in our model system.

Chronic and progressive dying neurons are the major feature of Alzheimer’s disease that can best explain the clinical symptoms. More than 20 years of intensive research has implicated two toxic peptides generated from a larger normal protein as playing an important role in the disease process. It is not known, however, if these peptides are a cause of the disease or just an effect of some other problem in brain cells. Our work is designed to investigate the role of these peptides, both alone and in combination, as direct causes of chronic brain cell death. We will accomplish this by using a simplified genetically controlled model organism. We also believe that our preliminary observations indicate a new cellular pathway that may be responsible for Alzheimer’s related cell death. We will thus try and prove this hypothesis using genetic and drug based experimental strategies in our model system. If this new pathway is indeed responsible for cell death in Alzheimer’s disease our work could lead to the identification of new treatment and prevention strategies.

Progress Updates

Accumulation of beta-amyloid (Aβ) protein is thought to be one cause of Alzheimer’s disease. Using a genetic model organism (Drosophila melanogaster—also known as the “fruit fly), Dr. Paul Salvaterra and colleagues established a link between Aβ accumulation and abnormal cell maintenance activity, called autophagy. Autophagy maintains cells in a stable, constant condition, as well as protects them from various kinds of stress. Dr. Salvaterra demonstrated that expression in fly brains of one type of beta-amyloid protein, called Aβ42, but not another type, called Aβ40, causes a massive increase in abnormal autophagy activity that appears to lead to neurodegeneration. Counterintuitive to current assumptions about autophagy, Dr. Salvaterra demonstrated that decreased activity results in less Aβ42 accumulation while increased activity seems to contribute to a greater rate of neurotoxicity. These results suggest that Aβ42-dependent abnormal autophagy may be a key cellular event driving neurodegeneration in Alzheimer’s disease.