TNF-α-NF-κB activation through pathological α-Synuclein disrupts the BBB and exacerbates axonopathy

초록

Dysfunction of the blood-brain barrier (BBB) is recognized as a key factor in the progression of neurodegenerative diseases (NDs), but the detailed mechanisms behind its pathogenesis and impact on neurodegeneration remain elusive. This study aimed to reveal the pathological effects of alpha-Synuclein (alpha-Syn), an aggregation protein in synucleinopathy, on BBB integrity and function and identify therapeutic targets for alpha-Syn-related vasculopathy. Using a brain endothelial cell model, we investigated the pathological effect of preformed fibril alpha-Syn (PFF) on BBB integrity, employing generative adversarial network (GAN) deep learning to analyze pathological changes. We found that PFF activates immune responses, increasing endothelial monolayer permeability via the TNF-alpha-NF-kappa B pathway. Further in vivo studies with PFF induced alpha-synucleinopathy, and a transgenic animal model (G2-3) revealed that alpha-Syn aggregation disrupts the BBB, leading to axonal degeneration that was mitigated by treatment with a non-BBB-penetrating TNF-alpha inhibitor, etanercept. These findings suggest that targeting brain endothelial TNF-alpha signaling could be a potential therapeutic approach for synucleinopathy-related NDs.

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