RAGE-A beta interactions in the pathophysiology of Alzheimer's disease

RAGE is a cell surface molecule primarily identified for its capacity to bi nd advanced glycation end-products and amphoterin. Immunocytochemical studi es demonstrated that in Alzheimer's disease (AD) the expression of RAGE is elevated in neurons close to neuritic plaque beta-amyloid (A beta) deposits and in the cells of A beta containing vessels. Gross-linking of surface bo und A beta 1-40 to endothelial cells, yielded a band of 50 kDa identified a s RAGE. Using the soluble extracellular domain of recombinant human RAGE, w e found that A beta binds to RAGE with a Kd = 57 +/- 14 nM, a value close t o those found for mouse brain endothelial cells and rat cortical neurons. T he interaction of A beta with RAGE in neuronal, endothelial, and RAGE-trans fected COS-1 cells induced oxidative stress, as assessed by the TEARS and M TT assays. ELISA demonstrated a 2.5 times increase of RAGE in AD over contr ol brains. Activated microglia also showed elevated expression of RAGE. In the BV-2 microglial. cell line, RAGE bound A beta in a dose dependent manne r with a Kd of 25 +/- 9 nM. Soluble A beta induced the migration of microgl ia along a concentration gradient, while immobilized A beta arrested this m igration. A beta-RAGE interaction also activated NF-kappa B, resulting in n euronal up-regulation of macrophage-colony stimulating factor (M-CSF) which also induced microglial migration. Taken together, our data suggest that R AGE-A beta interactions play an important role in the pathophysiology of Al zheimer's disease.