Ferroptosis, a regulated form of iron-dependent cell death driven by lipid peroxidation, has emerged as a key mechanism implicated in neurodegenerative diseases, including Alzheimer’s disease (AD) [1,2]. Concurrently, disruptions in immunometabolism—the interplay between metabolic processes and immune cell function—play a critical role in the neuroinflammatory environment of AD [3]. However, the crosstalk between ferroptosis and immunometabolism in AD remains poorly understood.

Aims

The overarching aim of this PhD study is to elucidate the mechanistic link between ferroptosis and immunometabolic reprogramming in AD. Specific aims include:

1. Identify immune cells undergo ferroptosis in AD pathogenesis.

2. Investigate the molecular mechanism of how immunometabolism drives ferroptosis in the immune cells

3. Characterise the link between ferroptosis and lipid metabolism in human AD brains.

We will employ human-derived neuronal and glial cell lines treated with ferroptosis inducers and inhibitors to characterize changes in lipid metabolism, iron handling, and pro-inflammatory cytokine release. Single-cell transcriptomics and metabolomics will be used to map ferroptosis-driven metabolic shifts in immune and neuronal cell populations. Complementary experiments in humanised AD mouse models, will evaluate the contribution of ferroptosis to amyloid-beta (Aβ) and tau pathology, microglial activation, and synaptic loss. In parallel, immunohistochemical and biochemical analyses of post-mortem AD brain samples will validate findings, focusing on ferroptotic markers, iron accumulation, and metabolic enzyme alterations in brain regions most affected by AD.

The study’s outcomes will shed light on the interplay between ferroptosis and immunometabolism in AD pathogenesis, potentially identifying novel biomarkers and therapeutic targets. By integrating cellular, animal, and human data, this research aims to provide a comprehensive understanding of how ferroptosis influences neuroinflammation and neuronal loss in AD, paving the way for innovative treatment strategies targeting these intertwined processes.