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 (Aβ) deposits and in the cells of Aβ containing vessels. Cross-linking of surface bound Aβ 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 Aβ 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 Aβ 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 Aβ in a dose dependent manner with a Kd of 25 ± 9 nM. Soluble Aβ induced the migration of microglia along a concentration gradient, while immobilized Aβ arrested this migration. Aβ- RAGE interaction also activated NF-κB, resulting in neuronal up-regulation of macrophage-colony stimulating factor (M-CSF) which also induced microglial migration. Taken together, our data suggest that RAGE-Aβ interactions play an important role in the pathophysiology of Alzheimer's disease.
|Number of pages||7|
|Journal||Restorative Neurology and Neuroscience|
|Publication status||Published - 1998 Jun|
All Science Journal Classification (ASJC) codes
- Developmental Neuroscience
- Clinical Neurology