RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
Abstract
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.
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Under pathological conditions, RAGE mediates reentry or influx of circulating Aβ across the blood-brain barrier into the brain.
“Under pathological conditions, RAGE mediates reentry or influx of circulating A 𝛃 across the BBB into the brain, which is associated with neuroinflammatory response, CBF reductions, and BBB breakdown (134, 136)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [134]
RAGE-mediated reentry or influx of circulating Aβ across the blood-brain barrier is associated with neuroinflammatory response, cerebral blood flow reductions, and blood-brain barrier breakdown.
“which is associated with neuroinflammatory response, CBF reductions, and BBB breakdown (134, 136)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [134]
RAGE expression at the blood-brain barrier is increased in Alzheimer's disease and Alzheimer's disease models.
“Its expression at the BBB is increased in AD and AD models (134, 152, 410).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [134]
The receptor for advanced glycation end products (RAGE) is expressed mainly at the luminal membrane of the blood-brain barrier.
“In contrast to lipoprotein receptors, the receptor for advanced glycation end products (RAGE) is expressed mainly at the luminal membrane of the BBB (134).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [134]
RAGE expression is increased in Alzheimer's disease brain endothelium and mural cells.
“In contrast to LRP1, expression of RAGE, a major A 𝛃 influx receptor, is increased in AD brain endothelium and mural cells (134, 152, 410)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [134]
Increased RAGE expression likely contributes to circulating amyloid-beta influx, neuroinflammation, and reduced cerebral blood flow in Alzheimer's disease.
“likely contributing to circulating A 𝛃 influx, neuroinflammation, and reduced CBF (134, 136).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [134]
Blocking RAGE at the BBB reduces Aβ reentry into the brain, inhibits neuroinflammation, and improves CBF in a mouse model of AD.
“On the other hand, blocking RAGE at the BBB (134) effectively reduces A 𝛃 reentry into the brain, inhibits neuroinflammation, and improves CBF in a mouse model of AD (134, 136).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [134]
The three RAGE forms bind various ligands with similar affinities, including AGEs and amyloid β peptide.
“The three RAGE forms bind various ligands with similar affinities, including multiple advanced glycation end-products (AGEs) and amyloid β peptide31–37.”
From Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice (2019) · cites this paper as [34]
Exogenous amyloid β can reduce cerebral blood flow.
“Exogenous amyloid β can reduce cerebral blood flow (10–12)”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [11]
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Self-citationBrain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides
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Self-citationActive and passive immunotherapy for neurodegenerative disorders
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Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice
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- Authors
- Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., Zhu, H., Ghiso, J., Frangione, B., Stern, A., Schmidt, A. M., Armstrong, D. L., Arnold, B., Liliensiek, B., Nawroth, P., Hofman, F., Kindy, M., Stern, D., & Zlokovic, B.
- Affiliations
- University of Rochester Medicine (US)
- University of Southern California (US)
- Columbia University (US)
- University of Kentucky (US)
- NYU Langone Health (US)
- Heidelberg University (DE)
- Augusta University (US)
- ORCID
- Venue
- Nature Medicine
- Published
- 2003-06-15
- Volume
- 9
- Issue
- 7
- Pages
- 907-913
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2041851050
- Semantic Scholar
- e9e0f432fdaa5568ab57545cf04bdaf5bc89b0b6
- Cited by
- 1,426
- References
- 47
- Citations by year
- 2026: 52 · 2025: 60 · 2024: 56 · 2023: 74 · 2022: 77 · 2021: 88 · 2020: 89 · 2019: 68 · 2018: 68 · 2017: 68 · 2016: 69 · 2015: 76 · 2014: 70 · 2013: 60 · 2012: 72
- FWCI
- 16.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG16223)
- National Institute of Neurological Disorders and Stroke (NS34467)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- amyloid-beta, receptor for advanced glycation end products, RAGE, blood-brain barrier, amyloid-beta transport, cerebral amyloidosis, endothelin-1, vasoconstriction, inflammatory cytokines, Alzheimer's disease, dementia, cerebral blood flow
- MeSH terms
- Receptor for Advanced Glycation End Products, Aged, Aged, 80 and over, Animals, Blood-Brain Barrier, Brain, Cerebrovascular Circulation, Humans, Mice, Transgenic, Oligopeptides, Peptide Fragments, Receptors, Immunologic, Cytokines, Amyloid beta-Peptides, Endothelin-1, Protein Transport, Receptor, Endothelin A, Mice, Endothelin Receptor Antagonists
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