The copper-amyloid-beta-peptide complex of Alzheimer’s disease: affinity, structure, fibril formation and toxicity
Abstract
Senile plaques of Alzheimer’s disease (AD) patients are composed primarily of the
amyloid-β-peptide peptide (Aβ), and within these plaques Cu2+ ions are found
concentrated and directly bound to Aβ. Cu2+ homeostasis is severely impaired in AD
patients and recent in vivo studies implicate Cu2+ in the etiology of AD. However the
role of Cu2+ ions in AD is currently highly disputed due to the low reported affinity
of Aβ for Cu2+ (nM and μM), and Cu2+ binding to Aβ is thought to result in
amorphous aggregation rather than fibril formation. These two aspects, along with
the coordination geometry, stoichiometry and toxicity of the Cu2+-Aβ complex were
investigated in this thesis. In Chapter 3, circular dichroism and fluorescence
spectroscopy alongside competitive metal capture show a surprisingly high
picomolar affinity for both monomeric and fibrillar Aβ. In Chapter 4 electron
paramagnetic resonance was used to study the structure and stoichiometry of the
copper-Aβ complex in both monomeric and fibrillar Aβ. Both Aβ forms were able
to bind a full stoichiometric complement of Cu2+ ions, with identical square planar
coordination geometry. Importantly Cu2+ ion binding did not disrupt fibril structure.
In Chapter 5 of this thesis it is shown that, in contrast to the predominant belief in
the AD field, stoichiometric and sub-stoichiometric amounts of Cu2+ actually
accelerate the rate of fibril formation. Finally, the toxic effects of Aβ and Cu2+ were
studied in a PC12 clonal cell line. The presence of Cu2+ ions were found to enhance
Aβ cell toxicity, and substoichiometric concentrations of Cu2+ were found to be the
most toxic, suggesting that Cu2+ induced fibril formation and Cu2+ induced toxicity
may be linked. Therefore this study finds considerable support for an altered
amyloid hypothesis where Cu2+ dyshomeostasis has a central role in AD.
Authors
Sarell, Claire JessicaCollections
- Theses [3834]