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RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain

Nature Medicine volume 9, pages 907–913 (2003)Cite this article

Abstract

Amyloid-β peptide (Aβ) interacts with the vasculature to influence Aβ levels in the brain and cerebral blood flow, providing a means of amplifying the Aβ-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Aβ infusion and studies in genetically manipulated mice show that Aβ interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Aβ across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Aβ-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Aβ in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Aβ-vascular interactions, including development of cerebral amyloidosis.

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Figure 1: RAGE-dependent Aβ transport at the BBB.
Figure 2: RAGE-dependent Aβ transport induces neurovascular stress.
Figure 3: Soluble RAGE reduces cerebral amyloidosis in PD-hAPP mice.
Figure 4: RAGE-dependent effects of Aβ on cerebral blood flow.
Figure 5: Aβ-RAGE ligation suppresses CBF through ET-1.
Figure 6: RAGE blockade reverses cerebral blood flow in Tg2576 mice.

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Acknowledgements

This work was supported by grants from the US Public Health Service (AG16223 and NS34467). R.D., S.D.Y. and R.S.K. contributed equally to this work. D.S. and M.K. were cosenior authors and B.V.Z. was a senior author.

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Authors and Affiliations

  1. Department of Neurosurgery and Division of Neurovascular Biology, Frank P. Smith Laboratories for Neurosurgery, Center for Aging and Developmental Biology, University of Rochester Medical Center, Rochester, 14642, New York, USA

    Rashid Deane, Barbara LaRue, Deborah Welch, Lawrence Manness, Don L Armstrong & Berislav Zlokovic

  2. Departments of Pathology and Surgery, College of Physicians and Surgeons of Columbia University, New York, 10032, New York, USA

    Shi Du Yan, Chang Lin, Alan Stern, Ann Marie Schmidt & David Stern

  3. Departments of Neurosurgery and Pathology, University of Southern California School of Medicine, Los Angeles, 90033, California, USA

    Ram Kumar Submamaryan, Suzana Jovanovic, Elizabeth Hogg & Florence Hofman

  4. Department of Molecular and Cellular Biochemistry, University of Kentucky School of Medicine, Lexington, 40536, Kentucky, USA

    Jin Yu, Hong Zhu & Mark Kindy

  5. Department of Pathology, New York University Medical Center, New York, 10016, New York, USA

    Jorge Ghiso & Blas Frangione

  6. Departments of Internal Medicine and Institute for Cancer Research, University of Heidelberg, Grabengasee 1, Heidelberg, D-69117, Germany

    Bernd Arnold, Birgit Liliensiek & Peter Nawroth

  7. Dean's Office, Medical College of Georgia, Augusta, 30912, Georgia, USA

    David Stern

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Correspondence to Berislav Zlokovic.

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Deane, R., Du Yan, S., Submamaryan, R. et al. RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9, 907–913 (2003). https://doi.org/10.1038/nm890

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