Kavli Affiliate: Mark Ellisman
| Authors: Kelli Lauderdale, Zhaoqi Yan, Andrew S. Mendiola, Yutong Zhang, Dakota Mallen, Pranav Nambiar, Erica Brady, Stephanie R. Miller, Rosa Meza Acevedo, Belinda Cabriga, Fred Jiang, Nick Kaliss, Kevin Shen, Jia Shin, Jessica Herbert, Keran Ma, Jae Kyu Ryu, Ayushi Agrawal, Renaud Schuck, Maria del Pilar S. Alzamora, Jorge Sanz-Ros, Inma Cobos, Jeffrey Stavenhagen, Aaron B. Kantor, Mark H. Ellisman, Katerina Akassoglou and Jorge J. Palop
| Summary:
Brain network dysfunction—including hyperexcitability, altered oscillations, and sleep disruption—is prominent in Alzheimer’s 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 (Fggγ390–396A 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;Fggγ390–396A 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