Biomedical Frontiers: Fall 1997, Vol.4, No.2
RAGE in Alzheimer's Disease

The binding of amyloid-beta peptide to RAGE on neurons results in the expression of macrophage-colony stimulating factor (M-CSF), which mediates the attraction and activation of microglial cells observed in Alzheimer's disease. These results raise the possibility that low molecular inhibitors of RAGE might have neuroprotective effects in Alzheimer's disease.

RAGE is a cell surface receptor for non-enzymatically glycated structures that occur in diabetes (see "The RAGE in Diabetes," front cover) and for amyloid-beta peptide, which accumulates in the brain in Alzheimer's disease. The first recognition that RAGE might be involved in the pathogenesis of Alzheimer's disease was published in a study by CPMC researchers in the Aug. 22, 1996, issue of Nature.

Drs. Shi Du Yan, assistant professor of pathology; David Stern, professor of physiology and cellular biophysics in surgery; and Ann Marie Schmidt, assistant professor of medicine and surgery, reported that RAGE on neurons and microglial cells serves as a receptor for amyloid-beta peptide. The binding of amyloid-beta peptide to RAGE alters critical properties of neurons and microglia and may therefore play a part in the neurotoxicity characteristic of Alzheimer's.

"Although the event or events that initiate Alzheimer's disease have yet to be identified, this study shows that RAGE is probably an important factor in the progression of the disease," says Dr. Yan. The researchers had hypothesized the existence of a cell surface receptor that would focus the effects of amyloid-beta peptide on target cells but did not expect that receptor to be RAGE. "It was an incredible surprise to find it," says Dr. Schmidt. The researchers speculate that normally RAGE is involved in neuronal development early in life.