Background
Iron dyshomeostasis has been observed in Alzheimer’s Disease (AD) [1]. We have suggested that ferroptosis, a form of iron-enhanced programmed cell death, operates in AD [2], and arises from excess lethal lipids as detoxification mechanisms are overwhelmed [2]. We hypothesize that iron acts as an “accelerant” by enhancing lethal lipid production. Thus, attenuating iron levels while simultaneously increasing cellular detoxification may pose a novel putative therapeutic strategy for AD.
Aim
To develop state-of-the-art quantitative simultaneous mapping of brain iron and lethal lipids in the Alzheimer’s Disease brain towards identifying novel therapeutic targets.
Techniques and skills
Quantitative brain metal mapping by synchrotron radiation X-ray fluorescence
Quantitative mapping of brain lipids (lipidomics) by mass spectrometry or Raman imaging
Immunohistochemistry and microscopy
Annual Overarching Objectives
Year 1
Development of tissue preparation methods for acquisition of iron and lipid maps, including training in techniques.
Development of analysis methods for information-rich lipid maps (lipidomics data), including training in image analysis.
Training in quantitative analysis of iron mapping data.
Year 2
Co-registration of multimodality data
Development of artificial intelligence methods to enhance lipidomic and metal characterisation.
Data collection from human brain samples from AD and age-matched cognitively normal subjects
Quantification of iron mapping data
Year 3
Analysis and quantification of experimental data including identification and quantification of toxic lipids and their precursors.
Writing research papers and thesis
References
[1] A Ashraf, M Clark, P-W So (2018). The aging of iron man. Fronts Aging Neursci. 10: 65.
[2] A Ashraf, J Jeandriens, HG Parkes, P-W So (2020). Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in Alzheimer’s disease: evidence of ferroptosis. Redox Biol 32: 101494.