Myelin–axon interface vulnerability in  Alzheimer’s disease revealed by subcellular  prMyelin–axon interface vulnerability in  Alzheimer’s disease revealed by subcellular  proteomics and imaging of human oteomics and imaging of human and  mouse brain

Myelin-axon interface vulnerability in Alzheimer’s disease revealed by subcellular proteomics

and imaging of human and mouse brain

Yifei Cai  1 , Iguaracy Pinheiro-de-Sousa  2,17, Mykhaylo Slobodyanyuk  3,4,17, Fuyi Chen1,17, Tram Huynh1, Jean Kanyo5, Peiyang Tang1, Lukas A. Fuentes6, Amber Braker7, Rachel Welch7, Anita Huttner8, Lei Tong1, Peng Yuan  1,16, TuKiet T. Lam  5,9,10, Evangelia Petsalaki  2, Jüri Reimand  3,4,11, Angus C. Nairn  10,12,13 & Jaime Grutzendler  1,14,15

Abstract

Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer’s disease (AD), disruptions in

myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics

of the myelin–axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple

dysregulated signaling pathways and ligand–receptor interactions, including those linked to amyloid-β processing, axonal outgrowth and lipid

metabolism. Expansion microscopy confirmed the subcellular localization of top proteomic hits and revealed amyloid-β aggregation within the

internodal periaxonal space and paranodal/juxtaparanodal channels. Although overall myelin coverage is preserved, we found reduced paranode

density, aberrant myelination and altered paranode positioning around amyloid-plaque-associated dystrophic axons. These findings suggest

that the myelin–axon interface is a critical site of protein aggregation and disrupted neuro-glial signaling in AD.

原文链接：https://doi.org/10.1038/s41593-025-01973-8