Nature Medicine
9, 907 - 913 (2003)
Published online: 15 June 2003; | doi:10.1038/nm890
RAGE mediates amyloid- peptide transport across the blood-brain barrier and accumulation in brainRashid Deane1, Shi Du Yan2, Ram Kumar Submamaryan3, Barbara LaRue1, Suzana Jovanovic3, Elizabeth Hogg3, Deborah Welch1, Lawrence Manness1, Chang Lin2, Jin Yu4, Hong Zhu4, Jorge Ghiso5, Blas Frangione5, Alan Stern2, Ann Marie Schmidt2, Don L Armstrong1, Bernd Arnold6, Birgit Liliensiek6, Peter Nawroth6, Florence Hofman3, Mark Kindy4, David Stern2, 7
& Berislav Zlokovic11
Frank P. Smith Laboratories for Neurosurgery, Department of Neurosurgery and Division of Neurovascular Biology, Center for Aging and Developmental Biology, University of Rochester Medical Center, Rochester, New York 14642, USA. 2
Departments of Pathology and Surgery, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. 3
Departments of Neurosurgery and Pathology, University of Southern California School of Medicine, Los Angeles, California 90033, USA. 4
Department of Molecular and Cellular Biochemistry, University of Kentucky School of Medicine, Lexington, Kentucky 40536, USA. 5
Department of Pathology, New York University Medical Center, New York, New York 10016, USA. 6
Departments of Internal Medicine and Institute for Cancer Research, University of Heidelberg, Grabengasee 1, D-69117 Heidelberg, Germany. 7
Dean's Office, Medical College of Georgia, Augusta, Georgia 30912, USA.
Correspondence should be addressed to Berislav Zlokovic Berislav_Zlokovic@urmc.rochester.eduAmyloid- peptide (A) interacts with the vasculature to influence A levels in the brain and cerebral blood flow, providing a means of amplifying the A-induced cellular stress underlying neuronal dysfunction and dementia. Systemic A infusion and studies in genetically manipulated mice show that A interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of A across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating A-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of A in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of A-vascular interactions, including development of cerebral amyloidosis.
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