Iron is vital for healthy brain function. However when present in a redox-active form or in excess concentrations it can be toxic. Interestingly, increased levels of redox-active iron biominerals have been shown to exist in Alzheimer’s disease (AD) tissues, including lesions comprised of the AD peptide β-amyloid (Aβ). These iron phases are capable of producing reactive oxygen species, resulting in the generation of oxidative stress manifesting as neuronal injury. As oxidative stress and the accumulation of iron are recognised as early stage events in AD, the presence of redox-active iron may prove fundamental in the development of AD pathology. The origin of these redox-active iron biominerals is unclear but recent studies suggest their formation may involve the interaction of Aβ with unbound brain iron and/or the malfunction of the iron storage protein ferritin. Despite these observations, the relationship between Aβ and iron is poorly understood, and the products of Aβ/iron interaction remain unknown. In this thesis, synchrotron-based x-ray techniques are combined with traditional biological approaches to examine the interactions between Aβ and various synthetic and naturally occurring iron forms. Through this methodology Aβ is shown to incorporate ferric iron phases into its fibrillar structure in vitro, with this interaction resulting in the chemical reduction of iron into a redox-active state. Further to this, Aβ is demonstrated to disrupt ferritin structure resulting in the chemical reduction of its redox-inactive iron core in vitro. Additionally the interaction of Aβ with crystalline iron phases is shown destroy iron crystal structure. Finally, redox-active iron is shown to be associated with regions of AD pathology, including fibrillar Aβ-like structures, within a transgenic mouse model of AD in situ. These findings suggest an origin for the redox-active iron forms and oxidative stress previously witnessed in AD tissue, thereby shedding light on the process of AD pathogenesis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:695605 |
| Date | January 2015 |
| Creators | Everett, James |
| Publisher | Keele University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.keele.ac.uk/2502/ |
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