Investigating the effects of iron and inflammation on the brain

Abstract

Iron is found in copious amounts in the brain and is commissioned with the task of performing pleiotropic functions including synthesis of neurotransmitters and adenosine triphosphate, and neuronal myelination. Perturbations in iron homeostasis are common features observed in the normal aging brain and Alzheimer’s disease. There have been reports of a novel form of iron-dependent cell death known as ferroptosis in cancer studies, but the evidence implicating ferroptosis in the normal and demented brain remains sparse. This thesis aims to investigate the age-related changes in brain iron (and metal) deposition with normal aging C57Bl/6J mice, and its association with glial cells, microglia, and astroglia. Since iron and inflammation are intimately related and share synergistic interactions, another aim was to study the effects of peripheral iron in the presence and absence of inflammation on the brain of C57Bl/6J mice and investigate proxy measures of ferroptosis. Moreover, the thesis aims to elucidate the associated ferroptotic-like changes (iron dyshomeostasis, altered anti-oxidant profile, lipid peroxidation) observed in the preclinical model and evaluate its translational implication in human post-mortem brain tissue obtained from cognitively normal and Alzheimer’s disease cases.
I demonstrate altered iron deposition and glial dystrophy with aging in C57Bl/6J mice, confirming my hypothesis of iron dyshomeostasis and inflammation. Mice primed with iron and subsequently exposed to inflammation demonstrated cognitive impairment, altered brain relaxation rates, iron dyshomeostasis, diminished levels of antioxidant proteins, lipid peroxidation, and inflammation. As hypothesized, I found evidence of ferroptosis in the form of iron dyshomeostasis, lipid peroxidation, and perturbed cystine/glutamate antiporter in the Alzheimer’s disease brains. My results suggest that the resurrection of iron homeostasis may hold therapeutic promise in aging and neurodegenerative diseases including AD. Ferroptosis may be a mechanism through which iron induces toxicity and warrants thorough investigation.

Date of Award	1 Feb 2021
Original language	English
Awarding Institution	King's College London
Supervisor	Po-Wah So (Supervisor), Gareth Barker (Supervisor), Gareth Barker (Supervisor) & Po-Wah So (Supervisor)