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bioRxiv · 10.64898/2026.06.11.731740

Vascular and synaptic proteomes reveal blood-brain barrier disruption and postsynaptic remodeling in human temporal lobe epilepsy

Spillard, G.·Zhang, M.·Atai, N. A.·Bosworth, A.·Clementel, V. A.·Russin, J. J.·Liu, C. Y.·Coba, M. P.·Rust, R.
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Abstract

Blood-brain barrier (BBB) dysfunction and mesial temporal lobe epilepsy (MTLE) are considered to be engaged in a pathological feedback loop, with the consequent worsening of both conditions. However, the molecular landscape of the disruptions at the synapse and the blood-brain barrier during MTLE remains poorly characterized. Here, we perform quantitative proteomics on paired brain microvessel and vessel-depleted postsynaptic density (PSD) enriched fractions isolated from the epileptic hippocampus and ipsilateral temporal pole of patients with drug-resistant MTLE. The microvessel fraction (1,541 proteins; 439 differentially expressed proteins (DEPs)) reveals loss of tight-junction and endothelial adhesion proteins together with pericyte markers, concurrent with a significant increase of fibrinogen, plasminogen, complement C3, GFAP, and enrichment for complement and coagulation cascades. The PSD enriched fraction (7,450 proteins; 1,881 DEPs) shows the consequences of BBB leakage with an increase of protein infiltration, alongside inflammatory and extracellular-matrix proteins, together with disruption of the pre- and postsynaptic signaling machinery and loss of GABAergic interneurons. Cross-referencing healthy-brain expression confirms that the dysregulation of the processes reflects disease-associated changes rather than regional differences. Immunohistochemistry confirms microvascular remodeling, pericyte loss, parenchymal fibrinogen extravasation, microglial activation and presynaptic marker depletion in the epileptic hippocampus. Ligand-receptor mapping reveals dysregulation of the neurovascular ECM-adhesion interface, with upregulated parenchymal ECM ligands and downregulated vascular integrin receptors. Network-proximity analyses nominate candidate disease-modifying compounds for reversing the combined vascular and synaptic MTLE signature. Together, these findings establish a molecular map of vascular and synaptic dysfunction in human MTLE.

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Spillard, G., Zhang, M., Atai, N. A., Bosworth, A., Clementel, V. A., Russin, J. J., Liu, C. Y., Coba, M. P., Rust, R.. 2026-06-16. Vascular and synaptic proteomes reveal blood-brain barrier disruption and postsynaptic remodeling in human temporal lobe epilepsy. https://doi.org/10.64898/2026.06.11.731740

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