New Clues To Early Neuron Damage In Alzheimer's Disease

October 15, 1997

NEW YORK, N.Y., Oct. 15, 1997--Columbia University College of Physicians & Surgeons scientists have discovered a molecule, called ERAB, that provides an important clue to how early neuron damage may occur in Alzheimer's disease. The findings, published in the Oct. 16, issue of Nature, may lead to a intracellular target for the eventual treatment of the disease.

Alzheimer's disease is a progressive neurodegenerative disorder in which nerve cells in the brain die. It is the fourth leading cause of death in the United States, affecting more than four million people. Scientists have long known that amyloid-beta peptide, a precursor protein involved in Alzheimer's disease, collects in sticky clumps called "neuritic plaques" outside of nerve cells in the brain, and eventually kills them. The discovery may allow scientists to develop therapies that inhibit the interaction of ERAB and amyloid-B peptide and protect neurons from damage.

Lead author Dr. Shi Du Yan, assistant professor in the department of pathology, and senior author Dr. David Stern, professor with joint appointments in the departments of physiology and cellular biophysics and surgery, discovered that neuronal damage in Alzheimer's disease takes place even before increased levels of amyloid-beta peptide accumulate outside of cells.

Since amyloid-beta peptide is produced within cells, scientists looked for targets within the cell via which the peptide causes early damage. Researchers identified the first intracellular target of amyloid-beta peptide and named it ERAB.

"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 Alzheimer's disease. In the traditional view, large extracellular accumulations of amyloid-beta peptide, as happens in the late stages of Alzheimer's disease, 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 may 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."

ERAB is found in a wide range of cells where scientists believe it is involved in the metabolism of fatty acids. The CPMC researchers found that when ERAB interacts with amyloid-beta peptide, it increases the toxicity of the peptide. The researchers also found that blocking the interaction of ERAB and amyloid-beta peptide protects cells from damage. "Given the apparent widespread distribution of ERAB throughout the body, this finding, while important in its own right -- for pointing toward mechanisms of amyloid-induced neurodegeneration, also has the potential to contribute to a more complete understanding of vascular dementia," says Dr. Stephen Snyder, Health Science Administrator for the Neuroscience and Neuropsychology of aging program at the National Institute on Aging.

The finding may allow scientists to develop therapies that inhibit the interaction of ERAB and amyloid-B peptide, protecting neurons from damage. Drs. Stern and Yan are now working to identify specific cellular targets of amyloid-beta peptide, which will help in creating such therapies.

The study's other authors were Xi Chen, Jin fu, Claudio Soto, Huaijie Zhu, Futwan Al-Mohanna, Kate Collison, Aiping Zhu, Eric Stern, Takaomi Saido, Masaya Tohyama, Satoshi Ogawa, and Alex Roher.

The study was funded by the National Institute on Aging (NIA), part of the National Institutes of Health, and the Columbia University department of surgery research fund.

Columbia University Medical Center

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