Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Selkoe, D.J. Clearing the brain's amyloid cobwebs. Neuron 32, 177–180 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Yan, S.D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Thomas, T., Thomas, G., McLendo, C., Sutton, T. & Mullan, M. β-amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 115–118 (1996).

    Article  Google Scholar 

  4. 4

    Shibata, M. et al. Clearance of Alzheimer's amyloid-β1–40 peptide from brain by low-density lipoprotein receptor-related protein-1 at the blood brain barrier J. Clin. Invest. 106, 1489–1499 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Zlokovic, B.V. et al. Clearance of amyloid-β-peptide from brain: transport or metabolism? Nat. Med. 6, 718–719 (2000).

    Article  PubMed  Google Scholar 

  6. 6

    Bading, J.R. et al. Brain clearance of Alzheimer's amyloid-β40 in the squirrel monkey: a SPECT study in a primate model of cerebral amyloid angiopathy. J. Drug Targeting 10, 359–368 (2002).

    CAS  Article  Google Scholar 

  7. 7

    DeMattos, R.B. et al. Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295, 2264–2267 (2002).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    DeMattos, R.B. et al. Plaque-associated disruption of CSF and plasma amyloid-β equilibrium in a mouse model of Alzheimer's disease. J. Neurochem. 81, 229–236 (2002).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Mackic, J.B. et al. Circulating amyloid-β peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer's disease lesions. Vasc. Pharmacol. 38, 303–313 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Zlokovic, B.V. et al. Blood-brain barrier transport of circulating Alzheimer's amyloid-β. Biochem. Biophys. Res. Commun. 197, 1034–1040 (1993).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Maness, L.M., Banks, W.A., Podlisny, M.B., Selkoe, D.J. & Kastin, A.J. Passage of human amyloid-β protein 1-40 across the murine blood-brain barrier. Life Sci. 55, 1643–1650 (1994).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Ghilardi, J.R. et al. Intra-arterial infusion of [125I]Aβ1–40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport 7, 2607–2611 (1996).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Martel, C.L. et al. Blood-brain barrier uptake of the 40 and 42 amino acid sequences of circulating Alzheimer's amyloid-β in guinea pigs. Neurosci. Lett. 206, 157–160 (1996).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Zlokovic, B.V. et al. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer's disease amyloid-β at the blood-brain and blood-cerebrospinal fluid barriers. Proc. Natl. Acad. Sci. USA 93, 4229–4236 (1996).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Martel, C.L. et al. Isoform-specific effects of apolipoproteins E2, E3, E4 on cerebral capillary sequestration and blood-brain barrier transport of circulating Alzheimer's amyloid β. J. Neurochem. 69, 1995–2004 (1997).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Mackic, J.B. et al. Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer's amyloid-β peptide in aged squirrel monkey with cerebral amyloid angiopathy. J. Neurochem. 70, 210–215 (1998).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Poduslo, J.F., Curran, G.L., Sanyal, B. & Selkoe, D.J. Receptor-mediated transport of human amyloid-β1-40 and 1-42 at the blood-brain barrier. Neurobiol. Dis. 6, 190–199 (1999)

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Wengenack, T.M., Curran, G.L. & Poduslo, J.F. Targeting Alzheimer amyloid plaques in vivo. Nat. Biotech. 18, 868–872 (2000).

    CAS  Article  Google Scholar 

  19. 19

    Ghersi-Egea, J.F. et al. Fate of cerebrospinal fluid-borne amyloid β-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries. J. Neurochem. 67, 880–883 (1996).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Monro, O.R. et al. Substitution at codon 22 reduces clearance of Alzheimer's amyloid-β peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood. Neurobiol. Aging 23, 405–412 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Sigurdsson, E.M. et al. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am. J. Pathol. 159, 439–447 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Matsuoka, Y. et al. Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to β-amyloid. J. Neurosci. 23, 29–33 (2003).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Carro, E. et al. Serum insulin-like growth factor I regulates brain amyloid-β levels. Nat. Med. 8, 1390–1397 (2002).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Hofmann, M.A. et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97, 889–901 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Yan, S.D. et al. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat. Med. 6, 643–651 (2000).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Mackic, J.B. et al. Human blood-brain barrier receptors for Alzheimer's amyloid-β 1-40: asymmetrical binding, endocytosis and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Invest. 102, 734–743 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Kawarabayashi, T. et al. Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J. Neurosci. 21, 372–381 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    DeMattos, R.B. et al. Potential role of endogenous and exogenous Aβ binding molecules in Aβ clearance and metabolism. in Aβ Metabolism in Alzheimer's Disease (ed. Saido, T.) 123–139 (Landes Bioscience, Georgetown, Texas, 2003).

    Google Scholar 

  29. 29

    Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Hsia, A. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228–3233 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Sakaguchi, T. et al. Central role for RAGE-dependent neointimal expansion in arterial stenosis. J. Clin. Invest. 111, 959–972 (2003)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Wyss-Coray, T. et al. TGF-β-1 promotes microglial amyloid clearance and reduces plaque burden in transgenic mice. Nat. Med. 7, 612–618 (2001).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Helme, R., Chen, H. & Khalil Z. Mechanisms underlying the vascular activity of Aβ(25-35) at the level of skin microvasculature. Brain Res. 736, 206–216 (1996).

    Article  PubMed  Google Scholar 

  34. 34

    Holtzman, D. et al. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. Ann. Neurol. 47, 739–747 (2000).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Takashi R.J. et al. Intraneuronal Alzheimer's Aβ42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 161, 1869–1879 (2002).

    Article  Google Scholar 

  37. 37

    Paris, D. et al. Soluble β-amyloid peptide mediate vasoactivity via activation of a pro-inflammatory pathway. Neurobiol. Aging 21, 183–197 (2000).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Niwa, K. et al. Aβ1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl. Acad. Sci. USA 97, 9735–9740 (2000).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Estrada, C., Gomez, C. & Martin, C. Effects of TNF-α on the production of vasoactive substances by cerebral endothelial and smooth muscle cells in culture. J. Cereb. Blood Flow Metab. 15, 920–928 (1995).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Tureen J. Effect of recombinant human tumor necrosis factor α on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. J. Clin. Invest. 95, 1086–1091 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Quehenberger P. et al. Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. Diabetes 49, 1561–1570 (2000).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Wautier, J-L. et al. Advanced glycation endproducts (AGEs) on the surface of diabetic red cells bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface associated AGEs and diabetic complications. Proc. Natl. Acad. Sci. USA 91, 7742–7746 (1994).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Wautier, J-L. et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy: soluble receptor for advanced glycation endproducts blocks hyperpermeability. J. Clin. Invest. 97, 238–243 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Niwa, K., Kazama, K., Younkin, S.G., Carlson, G.A. & Iadecola, C. Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol. Dis. 9, 61–68 (2002).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Maeda, K., Mies, G., Olah, L. & Hossmann, K.-A. Quantitative measurement of local cerebral blood flow in the anesthetized mouse using intraperitoneal [14C]iodontipyrine injection and final arterial heart blood sampling. J. Cereb. Blood Flow Metab. 20, 10–14 (2000).

    CAS  Article  PubMed  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Berislav Zlokovic.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing