Myelin-axon interface disruption uncovered by subcellular proteomics and imaging of Alzheimer’s human brain

ABSTRACT: Myelin ensheathment enables efficient axonal electrical conduction, metabolic support, and regulates neuronal plasticity. Myelin and axon disruptions are involved in Alzheimer’s disease (AD), however, the precise mechanisms of how myelin and axons are decoupled remain poorly understood. Using novel subcellular proximity labeling proteomics, we characterizeduncovered the myelin-axon interface proteomeics in AD human postmortem brains and unaffected controls. We identified AD-dysregulated ligand-receptors and downstream signaling, such as amyloid processing and axonogenesis, that are involved in myelin-axon interaction. Using high resolution imaging approaches, we revealed structural abnormality of paranodes, and corroborated proteomic evidence showing intrusion of amyloid fibers at the internodal peri-axonal space and paranodal channels. We also revealed aberrant myelin and paranodes are associated with axonal spheroids around amyloid plaques. Together, this study reveals myelin-axon interface as a vulnerable site in AD, and provides novel techniques and resources to delineate the complex molecular and cellular interaction between myelin and axons in AD and beyond.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Yifei Cai  

LAB HEAD: Jaime Grutzendler

PROVIDER: PXD045861 | Pride | 2025-06-27

REPOSITORIES: Pride