The Emerging Role of Ferroptosis-Autophagy-Mitophagy in Alzheimer’s Disease Pathophysiology and Therapy

^1,1* Department of Biotechnology, Jaypee Institute of Information Technology, Noida, U.P., India
² Faculty of Health, Graduate School of Health, University of Technology Sydney, Australia
³ Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia

Abstract

Alzheimer’s disease (AD) is emerging as a pathological state characterized by dysregulated proteostasis and metabolic homeostasis, in which oxidative stress and mitochondrial dysfunction converge to accelerate neurodegeneration. Recent evidence suggests ferroptosis, an iron-dependent form of regulated cell death, as a critical inflammatory trigger, causing oxidative stress and neuronal loss in AD, which is explicitly mediated by dysregulated autophagy and mitophagy mechanisms. More specifically, aberrant ferritinophagy and impaired PINK1/Parkin-mediated mitophagy may promote labile iron accumulation, mitochondrial ROS generation, and lipid peroxidation, thereby reducing the ferroptosis threshold of susceptible neurons. To disentangle this dynamic, we advance a unified multi-omics approach combining transcriptomics, proteomics and metabolomics studies produced from extensive cohorts of AD with computational inference of causality via networks along with singlecell resolution. This approach allows identification of concordant and discordant ferroptosis-autophagy signatures that span multiple stages of the pathway and prioritization of causal hubs such as GPX4, NCOA4 and PINK1 and evaluate their relationships with cognitive decline. Connectivity mapping and structural modelling also facilitate finding and proving candidate therapeutics that help restore redox balance and mitophagy flux. Finally, complex systems-level Ordinary Differential Equation modeling of iron-ROS-lipid peroxide dynamics is a predictive scaffold for intervention testing. Combined, this multi-level approach identifies the mechanisms that drive the crosstalk between ferroptosis and autophagy pathways in AD and presents a systems-level matrix to find avenues for therapeutic intervention.