Yifei Cai (New Haven, CT / US), Iguaracy Pinheiro-de-Sousa (Cambridge / GB), Mykhaylo Slobodyanyuk (Toronto / CA), Fuyi Chen (New Haven, CT / US), Tram Huynh (New Haven, CT / US), Jean Kanyo (New Haven, CT / US), Peiyang Tang (New Haven, CT / US), Lukas A. Fuentes (New Haven, CT / US), Amber Braker (New Haven, CT / US), Rachel Welch (New Haven, CT / US), Anita Huttner (New Haven, CT / US), TuKiet Lam (New Haven, CT / US), Evangelia Petsalaki (Cambridge / GB), Jüri Reimand (Toronto / CA), Angus C. Nairn (New Haven, CT / US), Jaime Grutzendler (New Haven, CT / US)
Myelin ensheathment is critical for rapid axonal electrical conduction, metabolic support and neuronal plasticity. Myelin and axonal pathology are observed in Alzheimer"s disease (AD), but the precise mechanisms are not well understood. Using novel proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains, we discovered dysregulation of signaling pathways and ligand-receptor pairs in AD, including β-amyloid processing, axonal outgrowth and lipid metabolism. Expansion Microscopy revealed intrusion of amyloid fibers into the internodal peri-axonal space and paranodal channels. Additionally, we observed aberrant myelination and paranode positioning at plaque-associated axonal spheroids as well as an overall reduction in paranode density without overt myelin loss. These findings highlight the myelin-axon interface as a potential site of significant protein aggregation and disruption of neuro-glial communication in AD. The proteomics dataset has uncovered the molecular architecture of the myelin-axon interface, paving the way for future mechanistic studies in health and disease.