RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.
Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.
Deane
Rashid
R
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.
Du Yan
Shi
S
Submamaryan
Ram Kumar
RK
LaRue
Barbara
B
Jovanovic
Suzana
S
Hogg
Elizabeth
E
Welch
Deborah
D
Manness
Lawrence
L
Lin
Chang
C
Yu
Jin
J
Zhu
Hong
H
Ghiso
Jorge
J
Frangione
Blas
B
Stern
Alan
A
Schmidt
Ann Marie
AM
Armstrong
Don L
DL
Arnold
Bernd
B
Liliensiek
Birgit
B
Nawroth
Peter
P
Hofman
Florence
F
Kindy
Mark
M
Stern
David
D
Zlokovic
Berislav
B
D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D044022:Receptor, Endothelin A; D011971:Receptors, Immunologic / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016207:Cytokines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D044022:Receptor, Endothelin A; D011971:Receptors, Immunologic; C087220:BQ 610