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P&S Journal

P&S Journal: Winter 1998, Vol.18, No.1
Research Reports
New Clues to Early Neuron Damage in Alzheimer's Disease

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 the cells. Now, P&S researchers have identified a molecule that enables amyloid-beta peptide to cause damage inside neurons. The findings, published in the Oct. 16, 1997, issue of Nature, may lead to a new cellular target for treatment of Alzheimer's disease.

Previous studies have found that people with Alzheimer's have increased levels of amyloid-beta peptide. The peptide accumulates outside of cells in sticky clumps known as neuritic plaques, a defining feature of the disease. However, scientists are now coming to believe that the first damage in Alzheimer's takes place even before the neuritic plaques develop. Since amyloid-beta peptide is produced within cells, scientists have been looking for targets within the cell through which the peptide could cause this early damage. Lead author Dr. Shi Du Yan, assistant professor of pathology, and senior author Dr. David Stern, 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 the endoplasmic reticulum and the mitochondria. ERAB is the first intracellular target of amyloid-beta peptide identified.

ERAB is normally found in a wide range of cells, where scientists believe it is involved in the metabolism of fatty acids. The researchers found that ERAB's interaction with amyloid-beta peptide increases the peptide's toxicity. The researchers also found that blocking this interaction protects cells from damage.

This study implicates ERAB as a participant in causing neuronal dysfunction in Alzheimer's disease,says Dr. Yan. The finding contributes to a newly emerging picture of how neuron damage occurs in the disease. In the traditional view, large extracellular accumulations of amyloid-beta peptide, as happens in the late stages of Alzheimer's, cause non-specific injuries to neurons. "But the identification of ERAB is one indication that in Alzheimer's disease, the earliest disturbances in neuronal function occur intracellularly and result from specific interactions of amyloid-beta peptide with molecular targets," says Dr. Stern. "Identifying such changes at an early stage may allow therapies to be initiated before neuronal loss and its severe consequences become manifest.

For example, the finding opens the way to therapies that inhibit the interaction of ERAB and amyloid-beta peptide, protecting neurons from damage. The scientists are now working to identify specific cellular targets of amyloid-beta peptide, which will help create such therapies.


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