Metals and Amyloids

We were the first group to show that beta amyloid (Aβ), the peptide implicated in the aetiology of Alzheimer’s disease, bound aluminium (Exley et al., (1993) FEBS Lett. 324, 293-295). We showed that binding abolished the α-helical conformation of Aβ in favour of random turn and Aβ-sheet conformations.

spherulites

Spherulites of ProIAPP1–48 formed in the presence of Al(III); A—spherulite showing the classical Maltese cross pattern of light extinction under the polarising microscope; B—spherulite showing positive staining for Congo red though C—no evidence of apple-green birefringence under crossed polarisers; D—spherulites under partial crossed polarisers and showing positive staining (purple) for Al(III). Scale bar is 200 μm in each of these images. From Exley, House, Patel, Wu and Fraser (2010).

 

Recent work by Dr (Pending) Matthew Mold and Prof Christopher Exley (2013) has shown that copper protects the brain from Alzheimer's  Plaques. Amyloid peptides were incubated with a markerr called Thioflavin T (ThT). The molecules of ThT sit happily in the grooves of the corrugated beta-sheets and give off a characteristic fluorescence, or glow, when excited by light. This glow is a dead giveaway that the beta-sheets are present in the samples.

When copper was added to the sample it glowed less, indicating that the beta-sheets failed to form.

 

For more information, please see the following references:

  1. Exley C, Price NC, Kelly SM & Birchall JD (1993) An interaction of beta-amyloid with aluminium in vitro . FEBS Letters, 324, 293-295.
  2. Exley C, Schley L, Murray S, Hackney CM & Birchall JD (1995) Aluminium, beta-amyloid and non-enzymatic glycosylation. FEBS Letters, 364, 182-184.
  3. Exley C (1996) In vitro toxicity of [beta]-amyloid. Biochemical Journal 314, 709.
  4. Exley C (1996) Amyloid, aluminium and the aetiology of Alzheimer's disease. Medical Journal of Australia 164, 252-253.
  5. Exley C & Birchall JD (1996) Biological availability of aluminium in commercial ATP. Journal of Inorganic Biochemistry 63, 241-252.
  6. Exley C (1997) ATP-promoted amyloidosis of an amyloid beta peptide. Neuroreport 8, 3411-3414.
  7. Exley C & Korchazhkina O (2001) Promotion of formation of amyloid fibrils by aluminium adenosine triphosphate (AlATP). Journal of Inorganic Biochemistry 84, 215-224.
  8. Exley C & Korchazhkina OV (2001) Plasmin cleaves A[beta]42 in vitro and prevents its aggregation into [beta]-pleated sheet structures. Neuroreport 12, 2967-2970.
  9. Exley C & Korchazhkina O (2001) The association of aluminium and beta amyloid in Alzheimer’s disease. In; Aluminium and Alzheimer’s Disease: The Science that Describes the Link (Editor; C Exley) Elsevier Science, Amsterdam, The Netherlands. p421-433.
  10. Korchazhkina OV, Ashcroft AE, Kiss T & Exley C (2002) The degradation of A[beta]25-35 by the serine protease plasmin is inhibited by aluminium. Journal of Alzheimer’s Disease 4, 357-367.
  11. House E, Collingwood J, Khan A, Korchazhkina O, Berthon G & Exley C (2004) Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of A[beta]42 in a manner which may have consequences for metal chelation therapy in Alzheimer’s disease. Journal of Alzheimers Disease 6, 291-301.
  12. Khan A, Ashcroft AE, Korchazhkina OV & Exley C (2004) Metal-mediated formation of fibrillar ABri amyloid. Journal of Inorganic Biochemistry 98, 2006-2010.
  13. Khan A, Ashcroft AE, Higenell V, Korchazhkina OV & Exley C (2005) Metals accelerate the formation and direct the structure of amyloid fibrils of NAC. Journal of Inorganic Biochemistry 99, 1920-1927.
  14. Exley C (2005) The Aluminium-Amyloid Cascade Hypothesis and Alzheimer’s Disease. In; Alzheimer's Disease: Cellular and Molecular Aspects of Amyloid beta. Subcellular Biochemistry 38, (Eds. Harris R & Fahrenholz F) p 225-234.
  15. Khan A, Dobson J & Exley C (2006) The redox cycling of iron by A[beta]42. Free Radical Biology and Medicine 40, 557-569.
  16. Exley C (2006) Aluminium and iron, but neither copper nor zinc, are key to the precipitation of [beta]-sheets of A[beta]42 in senile plaque cores in Alzheimer’s disease. Journal of Alzheimer’s Disease 10, 173-177.
  17. Exley C & Esiri M (2006) Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK. Journal of Neurology Neurosurgery and Psychiatry 77, 877-879.
  18. Ward B, Walker K & Exley C (2008) Copper(II) inhibits the formation of amylin amyloid in vitro. Journal of Inorganic Biochemistry 102, 371-375.
  19. House E, Mold M, Collingwood J, Baldwin A, Goodwin S & Exley C (2009) Copper abolishes the [beta]-sheet secondary structure of pre-formed amyloid fibrils of A[beta]42. Journal of Alzheimer’s Disease 18, 811-817.
  20. Exley C, House E, Collingwood JF, Davidson M, Cannon D & Donald AM (2010) Spherulites of A[beta]42 in vitro and in Alzheimer’s disease. Journal of Alzheimer’s Disease 20, 1159-1165.
  21. Exley C, House E, Patel T, Wu L & Fraser PE (2010) Human pro-islet amyloid polypeptide (ProIAPP1-48) forms amyloid fibrils and amyloid spherulites in vitro. Journal of Inorganic Biochemistry 104, 1125-1129.
  22. House E, Jones K and Exley C (2011) Spherulites in human brain tissue are composed of beta sheets of amyloid and resemble senile plaques. Journal of Alzheimer’s Disease 25, 43-46.
  23. Mold M, Shrive AK and Exley C (2012) Serum amyloid P component accelerates the formation and enhances the stability of amyloid fibrils in a physiologically significant under-saturated solution of A[beta]42. Journal of Alzheimer’s Disease (In the press.)
  24. Exley C (2012) The Coordination chemistry of aluminium in neurodegenerative disease. Coordination Chemistry Reviews (In the press)
  25. Mold M., Ouro-Gnao L., Wieckowski B.M. & Exley C. (2013). Copper prevents amyloid-β1–42 from forming amyloid fibrils under near-physiological conditions in vitro, Scientific Reports.