The Reporter: December 1997, Vol.8, No.5
Research notes
New Clues to Alzheimer's

 Scientists have long known that amyloid-beta peptide, a precursor protein involved in Alzheimer's disease, collects outside of nerve cells in the brain, eventually killing them. Now, P&S researchers have identified a molecule that enables amyloid-beta peptide to cause damage inside neurons. The findings may lead to a new cellular target for the eventual treatment of Alzheimer's disease.

 Previous studies found that people with Alzheimer's disease have increased levels of amyloid-beta peptide, which accumulates outside of cells in sticky clumps known as neuritic plaques. Scientists are now coming to believe that the first damage in Alzheimer's happens before neuritic plaques develop. Because amyloid-beta peptide is produced within cells, scientists have been looking for targets within the cell via which the peptide could cause early damage. Lead author Dr. Shi Du Yan, P&S assistant professor of pathology, and senior author Dr. David Stern, P&S professor of physiology and cellular biophysics and of surgery, identified such a target, a molecule they dubbed ERAB because of its location within the cell in structures known as the endoplasmic reticulum and the mitochondria. ERAB is the first intracellular target of amyloid-beta peptide ever identified.

 ERAB is normally found in a wide range of cells, where scientists believe it is involved in the metabolism of fatty acids. The P&S researchers found that when ERAB interacts with amyloid-beta peptide, it increases the toxicity of the peptide. They also found that blocking the interaction of ERAB and amyloid-beta peptide protects cells from damage.

 The finding contributes to an emerging picture of how neuron damage occurs in Alzheimer's disease. In the traditional view, large extracellular accumulations of amyloid-beta peptide, as happens in the disease's late stages, cause nonspecific injuries to neurons. The identification of ERAB is one indication that in Alzheimer's disease, the earliest disturbances in neuronal function occur intracellularly resulting from specific interactions of amyloid-beta peptide with molecular targets.