Uncovering Mechanisms of Myelin-Axon Pathology in Alzheimer's Disease

This project aims to delineate myelin-axon disruption in AD by using subcellular proteomics, iPSC modeling, advanced imaging and genetic manipulation, with the ultimate goal to identify molecular targets with therapeutic potential to reverse the myelin and axon pathology.

Myelin and axons interact reciprocally to enable fast signal transduction, neuronal plasticity, learning and memory. Myelin and axonal pathology are involved in Alzheimer’s disease (AD), however, the precise mechanisms of myelin-axon disruption remain poorly understood. This project aims to delineate the complex interaction between myelin and axons by using subcellular proteomics at the myelin-axon interface, iPSC modeling, intravital imaging and genetic manipulation, with the ultimate goal to identify molecular targets with therapeutic potential to reverse the myelin-axonal deficit in AD.

Our proposal reframes axonal spheroid pathology in Alzheimer’s disease by shifting focus from neurons alone to the myelin–axon interface, advancing the counterintuitive concept that aberrantly formed myelin actively worsens axonal degeneration rather than protecting against it. We are the first to combine proximity-labeling proteomics of human AD brains, oligocortical organoids, cell-type-specific AAV perturbations in oligodendrocytes, and intravital imaging into a unified framework linking extrinsic guidance cues and intrinsic cytoskeletal dysregulation to spheroid and myelin pathology.

The results of this project will provide mechanistic insight into myelin–axon interactions and their disruption in Alzheimer’s disease. This knowledge will advance our understanding of disease mechanisms and identify potential therapeutic targets. Furthermore, innovative tools developed through this project, including iPSC-derived models and AAV toolkits, will serve as valuable resources for studying myelin and axon pathology in neurodegeneration.