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P&S Journal

P&S Journal: Winter 1997, Vol.17, No.1
Research Reports
Receptor Cells Identified as Possible Cause of Neuronal Damage in Alzheimer's

I n two studies published in Nature, P&S researchers reported the identification of two different receptors on cells in the brain that may cause neuronal damage in Alzheimer's disease. In one study, supported by grants from the NIH and the American Heart Association/New York City Affiliate, authors Drs. Joseph El Khoury, John D. Loike, and Samuel C. Silverstein found that the scavenger receptor on microglial cells binds to fibrillar beta amyloid protein but not to its non-fibrillar form. Beta amyloid fibrils constitute the core of senile plaques in Alzheimer's disease, a pathological hallmark of the disease.

"This is the first identification of a cell surface receptor that differentiates between fibrillar beta amyloid and its non-fibrillar precursors," says Dr. Silverstein, the John C. Dalton Professor and Chairman of Physiology and Cellular Biophysics.

Microglial cells become immobilized when their scavenger receptors bind to fibrillar beta amyloid. This interaction initiates the secretion by microglia cells of chemicals, such as reactive oxygen species, that damage or kill surrounding neurons. The researchers also identified a peptide that blocks the interaction between microglial scavenger receptors and fibrillar beta amyloid.

Dr. Joseph El Khoury and his colleagues emphasized the generosity of Drs. Monty Krieger of Massachusetts Institute of Technology and Siamon Gordon of Oxford University, who provided important materials for this study, thereby speeding the progress of the research.

In the second study, supported by the NIH and the American Health Assistance Foundation, Drs. Shi Du Yan, David Stern, Ann Marie Schmidt, and others reported that the cellular Receptor for Advanced Glycation Endproducts (RAGE) binds amyloid-beta peptide. This peptide is the principal component of extracellular deposits of filamentous proteins in Alzheimer's disease whose enhanced presence correlates with neuronal dysfunction and dementia. RAGE is found on endothelial, neuronal, and microglial cells in the brain and to an enhanced degree in affected areas in Alzheimer's disease.

The consequences of amyloid-beta peptide-RAGE interaction include increased cellular oxidant stress and microglial activation (manifested by cytokine production, chemotaxis, and haptotaxis). In the presence of reagents that block access of amyloid-beta peptide to cellular RAGE, these pathologic effects were abolished. These findings suggest that amyloid-beta peptide interaction with RAGE may represent a novel target of therapeutic intervention in Alzheimer's disease.


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