- Title
- Does brain iron elevation modify the course of functional and pathological changes in mouse models of Alzheimer’s disease amyloidosis and Parkinson’s disease?
- Creator
- Acquah, Elvis Freeman
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Brain iron elevation has been observed in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) but it remains unclear whether it is a primary cause or an epiphenomenon of these diseases. To investigate whether elevated brain iron has disease-modifying effects on AD or PD, our group has developed a novel mouse model that combines chronic brain iron elevation with predisposition to AD and a mouse model that combines chronic brain iron elevation with acute parkinsonism. Mice with chronic brain iron elevation with predisposition to AD (APP/PS1+Iron) were generated by cross-breeding Hfe-/-xTfr2mut (Iron) mice, which model the human iron loading disorder haemochromatosis and have simultaneous disruption of two important iron regulatory genes, the hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2) genes, with mice harbouring transgenes containing human familial AD causal mutations in amyloid precursor protein and presenilin-1 (APP/PS1). Iron did not modify the onset or course of AD in the APP/PS1 mice, with no significant effect of chronic elevated brain iron on spatial cognition and cognitive flexibility, as assessed by IntelliCage testing, and recognition memory, as assessed by novel object recognition testing. While iron did not modify AD-related β-amyloidosis, assessed by cross-polarised light microscopy of Congo-red stain with concurrent Perls’ staining for iron, or Aβ deposition, assessed by thioflavin-S fluorescence (p>0.05), APP/PS1+Iron mice had increased Aβ deposition compared with APP/PS1 mice by Congo-red fluorescence alone (p=0.005). More studies are required to confirm this under cross-polarised light microscopy. Unexpectedly, while iron did not exacerbate the effect of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), chronic brain iron elevation alone, in the absence of MPTP, caused PD-like features, with the Hfe-/-xTfr2mut mice having significant deficits in balance and motor coordination at 9 months, as assessed using rotarod and balance beam (p˂0.05). Consistently, there were fewer TH+ cells in the substantia nigra pars compacta (SNc) of the Hfe-/-xTfr2mut mice at both 3 and 9 months of age (p˂0.05). While no effect of brain iron elevation on the density of TH+ terminals in the caudate putamen complex (CPu) was found at either age, there seemed to be an age-dependent loss of TH+ terminals in the CPu of all the groups at 9 months. These findings suggest brain iron elevation correlates with PD-like features, suggesting that the Hfe-/-xTfr2mut mice can be used as a potential PD model in future studies. Follow-up studies need to be conducted to confirm and further explore these findings to help inform appropriate interventions targeting iron dysregulation during prevention or treatment of PD.
- Subject
- brain iron elevation; Alzheimer’s disease (AD); Parkinson’s disease (PD); hemochromatosis (Hfe)
- Identifier
- http://hdl.handle.net/1959.13/1502558
- Identifier
- uon:55243
- Rights
- This thesis is currently under embargo and will be available from 13.09.2024., Copyright 2021 Elvis Freeman Acquah
- Language
- eng
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