Affiliations: Department of Pathology, Surgery, Medicine and
Physiology, Columbia University, College of Physicians and Surgeons, New York,
NY 10032, USA | Parke Davis, Ann Arbor, MI 48105, USA | Haldeman Laboratory for Alzheimer's Disease Research,
Sun Health Research Institute, Sun City, AZ 85351, USA
Note: [] Corresponding author: Alex E. Roher, M.D., Ph. D., Sun Health
Research Institute, 10515 West Santa Fe Dr., Sun City, AZ 85351, USA. Tel.: +1
602 876 5465; Fax: +1 602 876 5698; E-mail: [email protected]
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
(AB) deposits and in the cells of AB containing vessels. Cross-linking of
surface bound AB 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 AB 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 AB 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 AB in dose dependent manner with a Kd of 25 ± 9 nM. Soluble
AB induced the migration of microglia along a concentration gradient, while
immobilized AB arrested this migration. AB-RAGE interaction also activated
NF-kB, resulting in neuronal up-regulation of macrophage-colony stimulating factor (M-CSF)
which also induced microglial migration. Taken together, our data suggest that
RAGE-AB interactions play an important role in the pathophysiology of
Alzheimer's Disease.
