title: RAGE-Abeta interactions in the pathophysiology of Alzheimer's disease.
abstract: RAGE is a cell surface molecule primarily identified for its capacity to bind advanced glycation end-products and amphoterin. Immunocytochemical studies demonstrated that in Alzheimer's Disease (AD) the expression of RAGE is elevated in neurons close to neuritic plaque beta-amyloid (Abeta) deposits and in the cells of Abeta containing vessels. Cross-linking of surface bound Abeta 1-40 to endothelial cells, yielded a band of 50 kDa identified as RAGE. Using the soluble extracellular domain of recombinant human RAGE, we found that Abeta binds to RAGE with a Kd = 57 +/- 14 nM, a value close to those found for mouse brain endothelial cells and rat cortical neurons. The interaction of Abeta with RAGE in neuronal, endothelial, and RAGE-transfected COS-1 cells induced oxidative stress, as assessed by the TBARS and MTT assays. ELISA demonstrated a 2.5 times increase of RAGE in AD over control brains. Activated microglia also showed elevated expression of RAGE. In the BV-2 microglial cell line, RAGE bound Abeta in dose dependent manner with a Kd of 25 +/- 9 nM. Soluble Abeta induced the migration of microglia along a concentration gradient, while immobilized Abeta arrested this migration. Abeta-RAGE interaction also activated NF-kappaB, resulting in neuronal up-regulation of macrophage-colony stimulating factor (M-CSF) which also induced microglial migration. Taken together, our data suggest that RAGE-Abeta interactions play an important role in the pathophysiology of Alzheimer's Disease.
authors.affiliation: Department of Pathology, Surgery, Medicine and Physiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Yan
authors.forename: D
authors.initials: D
authors.lastname: Stern
authors.forename: M D
authors.initials: MD
authors.lastname: Kane
authors.forename: Y M
authors.initials: YM
authors.lastname: Kuo
authors.forename: H C
authors.initials: HC
authors.lastname: Lampert
authors.forename: A E
authors.initials: AE
authors.lastname: Roher