An investigation into the effects of inorganic element status on the accumulation and deposition of amyloid in various diseases.

Lane, Edmund (2000) An investigation into the effects of inorganic element status on the accumulation and deposition of amyloid in various diseases. Doctoral thesis, University of Central Lancashire.

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Several human diseases are reported to be associated with amyloidogenic peptides and proteins, for example, β amyloid (Αβ) in senile plaques of Alzheimer's disease and β2 microglobulin (β2M) deposition in dialysis related amyloidosis. The major factor for amyloidosis appears to be an increase in the production of amyloidogenic proteins, resulting in the amyloid β sheet deposits. It is clear that conformational changes in amyloidogenic proteins lead to fibril formation and aggregation. Several trigger factors may be involved in the initiation and propagation of these amyloid deposits. Common components such as serum amyloid P component (SAP), glycosaminoglycans (GAGs) may be involved, and metals such as aluminium, copper, zinc and calcium have also been implicated. Metals have been shown to induce aggregations of amyloid and accelerate amyloid deposition. The present study involved the investigation of the effects of inorganic elements on the secondary structural integrity of amyloid proteins leading to aggregation and deposition.

The addition of Cu2+ Zn2+ C2+ and Αl3+ (>50 μM) to the amyloids, particularly Αβ(1-40) and β2M, showed some changes with a general decrease in a helix secondary structure and an increase in β sheets. Both the Αβ(l-40) and β2M peptides treated with physiological concentration of either Α13+, Ca2+ Cu2+ or Zn2+ combined with the physiological concentrations of various GAGs showed that they had a synergistic effect, indicating that GAGs could play a role in conjunction with metals. This has not been previously reported in the literature. The binding of GAGs to the amyloids could provide further binding sites for metal ions, leading to an alteration in the protein conformation. There is evidence in the literature for metals as trigger factors in the deposition of the Alzheimer's disease Αβ peptides, but not for the dialysis related β2M peptide. Similar changes occurred for the interaction of both Αβ(l-40) and β2M with metals and also with metals in the presence of GAGs. This suggests that similar mechanisms may be involved and that metals may have an underlying role in the general process of amyloidosis independent of the type of amyloid protein involved.

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