Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer disease-related hyperexcitability and brain network dysfunction

Lauderdale, K.; Yan, Z.; Mendiola, A. S.; Zhang, Y.; Mallen, D.; Nambiar, P.; Brady, E.; Miller, S. R.; Acevedo, R. M.; Cabriga, B.; Jiang, F.; Kaliss, N.; Shen, K.; Shin, J.; Herbert, J.; Ma, K.; Ryu, J. K.; Agrawal, A.; Schuck, R.; Alzamora, M. d. P. S.; Sanz-Ros, J.; Cobos, I.; Stavenhagen, J.; Kantor, A. B.; Ellisman, M. H.; Akassoglou, K.; Palop, J. J.

doi:10.64898/2026.05.01.722324

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bioRxiv · 10.64898/2026.05.01.722324

Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer disease-related hyperexcitability and brain network dysfunction

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Abstract

Brain network dysfunction--including hyperexcitability, altered oscillations, and sleep disruption--is prominent in Alzheimers disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fgg{gamma}390-396A mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fgg{gamma}390-396A mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis--currently under clinical evaluation with the humanized antibody THN391-- represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026).110 HIGHLIGHTSO_LIFibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD mice C_LIO_LIFibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD mice C_LIO_LIGenetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunction C_LIO_LIAnti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit C_LI

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Lauderdale, K., Yan, Z., Mendiola, A. S., Zhang, Y., Mallen, D., Nambiar, P., Brady, E., Miller, S. R., Acevedo, R. M., Cabriga, B., Jiang, F., Kaliss, N., Shen, K., Shin, J., Herbert, J., Ma, K., Ryu, J. K., Agrawal, A., Schuck, R., Alzamora, M. d. P. S., Sanz-Ros, J., Cobos, I., Stavenhagen, J., Kantor, A. B., Ellisman, M. H., Akassoglou, K., Palop, J. J.. 2026-05-06. Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer disease-related hyperexcitability and brain network dysfunction. https://doi.org/10.64898/2026.05.01.722324

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