Paranodal instability driven by axonal mitochondrial accumulation in ischemic demyelination and cognitive decline

Abstract

Subcortical ischemic demyelination is the primary cause of vascular cognitive impairment in the elderly. However, its underlying mechanisms remain elusive. Using a bilateral common carotid artery stenosis (BACS) mouse model and an in vitro cerebellar slice model treated with low glucose-low oxygen (LGLO), we investigated a novel mechanism of vascular demyelination. This work identified syntaphilin-mediated docking of mitochondria as the initial event preceding ischemic demyelination. This axonal insult drives paranodal retraction, myelin instability, and subsequent cognitive impairment through excessive oxidation of protein 4.1B by mitochondrial ROS. Syntaphilin knockdown reestablished the balance of mitochondrial axoplasmic transport, reduced axonal ROS burden, and consequently decreased the abnormal oxidation of protein 4.1B, an essential component that secures the Caspr1/contactin-1/NF155 complex tethered to the axonal cytoskeleton βII-Spectrin within paranodes. This ultimately protected the paranodal structure and myelin and improved cognitive function. Our findings reveal a distinct pathological characteristic of ischemic demyelination and highlight the therapeutic potential of modulating axonal mitochondrial mobility to stabilize myelin structures and improve vascular cognitive impairment.