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Considering the Vascular Hypothesis of Alzheimer’s Disease: Effect of Copper Associated Amyloid on Red Blood Cells

  • Heather R. Lucas
  • Joseph M. Rifkind
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 765)

Abstract

The vascular hypothesis of Alzheimer’s disease (AD) considers cerebral hypoperfusion as a primary trigger for neuronal dysfunction. We have previously reported that red blood cells (RBCs) bind amyloid, which are the characteristic deposits found in AD brains, and interact with amyloid on the vasculature [1–3]. Oxidative stress triggered by these RBC/amyloid interactions could impair oxygen delivery. Recent literature has implicated copper bound amyloid-β peptide (CuAβ) and the associated production of reactive oxygen species (ROS) as one of the primary factors contributing to AD pathology. In this work, we have investigated CuAβ generated RBC oxidative stress. Aβ1–40 peptide with a stoichiometric amount of copper bound was produced and compared to the metal-free form of the peptide. Different aggregation states of the peptides were isolated and incubated with RBCs for 15 h. Interestingly, CuAβ stimulated a pronounced increase in red cell oxidative stress as indicated by increased hemoglobin (Hb) oxidation, increased formation of fluorescent heme degradation products, and a decrease in RBC deformability. These findings demonstrate a potential role for CuAβ in promoting vascular oxidative stress leading to impaired cerebral oxygen delivery, which may contribute to neurodegeneration associated with AD.

Keywords

Copper–amyloid Deformability Heme degradation Hemoglobin Oxidative stress 

Notes

Acknowledgment

This research was supported by the Intramural Research Program of the NIH, National Institute on Aging.

References

  1. 1.
    Nagababu E, Usatyuk PV, Enika D et al (2009) Vascular endothelial barrier dysfunction mediated by amyloid-β proteins. J Alzheimers Dis 17:845–854CrossRefGoogle Scholar
  2. 2.
    Ravi LB, Poosala S, Ahn D et al (2005) Red cell interactions with amyloid-β1-40 fibrils in a murine model. Neurobiol Dis 19:28–37CrossRefGoogle Scholar
  3. 3.
    Ravi LB, Mohanty JG, Chrest FJ et al (2004) Influence of β-amyloid fibrils on the interactions between red blood cells and endothelial cells. Neurol Res 26:579–585CrossRefGoogle Scholar
  4. 4.
    Meyer-Luehmann M, Spires-Jones TL, Prada C et al (2008) Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724CrossRefGoogle Scholar
  5. 5.
    Lashuel HA, Hartley D, Petre BM et al (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418:291CrossRefGoogle Scholar
  6. 6.
    Rauk A (2008) Why is the amyloid β peptide of Alzheimer’s disease neurotoxic? Dalton Trans 14(10):1273–1282Google Scholar
  7. 7.
    Zatta P, Drago D, Bolognin S et al (2009) Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol Sci 30:346–355CrossRefGoogle Scholar
  8. 8.
    Gaggelli E, Kozlowski H, Valensin D et al (2006) Copper homeostasis and neurodegenerative disorders (Alzheimer’s, prion, and Parkinson’s diseases and amyotrophic lateral sclerosis). Chem Rev 106:1995–2044CrossRefGoogle Scholar
  9. 9.
    Stone J (2008) What initiates the formation of senile plaques? The origin of Alzheimer-like dementias in capillary haemorrhages. Med Hypotheses 71:347–359CrossRefGoogle Scholar
  10. 10.
    de la Torre JC (2002) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33:1152–1162CrossRefGoogle Scholar
  11. 11.
    Schrag M, Crofton A, Zabel M et al (2011) Effect of cerebral amyloid angiopathy on brain iron, copper, and zinc in Alzheimer’s disease. J Alzheimers Dis 24:137–149PubMedPubMedCentralGoogle Scholar
  12. 12.
    Shin S, Hou JX, Suh JS et al (2007) Validation and application of a microfluidic ektacytometer (RheoScan-D) in measuring erythrocyte deformability. Clin Hemorheol Micro 37:319–328Google Scholar
  13. 13.
    Nagababu E, Mohanty JG, Bhamidipaty S et al (2010) Role of the membrane in the formation of heme degradation products in red blood cells. Life Sci 86:133–138CrossRefGoogle Scholar
  14. 14.
    Rifkind JM, Ramasamy S, Manoharan PT et al (2004) Redox reactions of hemoglobin. Antioxid Redox Signal 6:657–666CrossRefGoogle Scholar
  15. 15.
    Nagababu E, Rifkind JM (1998) Formation of fluorescent heme degradation products during the oxidation of hemoglobin by hydrogen peroxide. Biochem Biophys Res Commun 247:592–596CrossRefGoogle Scholar
  16. 16.
    Nagababu E, Rifkind JM (2000) Reaction of hydrogen peroxide with ferrylhemoglobin: superoxide production and heme degradation. Biochemistry 39:12503–12511CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Molecular Dynamics SectionNational Institute on Aging, National Institutes of HealthBaltimoreUSA

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