The Effects of Iron and Inflammation on Alzheimer’s Disease in 5xFAD Mice

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Date
2023-09-01
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Saudi Digital Library
Abstract
Both neuroinflammation and iron dyshomeostasis feature in, and contribute to, Alzheimer’s disease (AD), and have been shown to interact synergistically. This thesis aims to investigate: 1) the short-term effect of peripheral iron administration on the progression of AD in 5xFAD and wildtype in both male and female mice and 2) the short/long term effects of peripheral iron administration, with and without inflammatory priming, on the progression of AD in 5xFAD and wildtype mice. A multimodality approach was used to assess the progression of AD: behavioural assessments to evaluate cognitive performance; in-vivo magnetic resonance imaging studies, relaxation rates R1 and R2, as putative indices of inflammation and iron accumulation, respectively; quantitative iron assessments and immunohistochemical assessments of both neuroinflammation and plaque deposition. Iron treatment led to increased numbers of plaques and microglia in the hippocampus accompanying cognitive impairment and higher levels of hippocampal iron in 5xFAD female mice. Conversely, 5xFAD male mice treated with iron demonstrated increased levels of plaque deposition, but cognitive impairment was not observed. Male and female mice had a differential response to iron treatment. In the short-term effect, hippocampal and cortical R1 were increased by lipopolysaccharide (LPS) treatment alone, and combined with iron, in wildtype mice. Moreover, microglial branch length and number of end points were higher in LPS and LPS + iron. Conversely, in 5xFAD mice, plaque deposition was increased post-iron and -LPS treatments in the hippocampus and cortex but reduced when the two treatments were combined (LPS+iron). In the long-term, hippocampal and cortical R2 were increased by LPS treatment in 5xFAD mice. Additionally, plaque deposition was higher by LPS, alone or combined with iron, along with an increase of iron concentration in the hippocampus. In the long term, R2 correlated with Aβ plaque deposition, and with iron content consistent with previous reports. I demonstrate sex- and region-dependent effects of peripheral inflammation and/or iron in 5xFAD mice and wildtype littermates. The data provides evidence for further study of iron dyshomeostasis and inflammation as potential therapeutic targets in AD.
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Keywords
Neuroimaging, MRI, Alzheimer's disease
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