Therapeutic targeting of fibrin–microglia interactions ameliorates Alzheimer’s disease-related hyperexcitability and brain network dysfunction
Year: 2026
Type: preprint
Abstract: 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 (Fgg γ390–396A 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 γ390–396A 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 HIGHLIGHTS Fibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD mice Fibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD mice Genetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunction Anti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit
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, Jorge J. Palop
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Deciphering molecular pathways of inhibitory interneuron dysfunction in Alzheimer's disease, Neurovascular Interactions: Mechanisms, imaging, therapeutic potential, Epigenomic regulation of oxidative stress-producing innate immunity in neuroinflammation, UC San Diego FIRST Program, Optogenetic dissection of cellular and circuit mechanisms of network dysfunction and amyloid deposition in mouse models of Alzheimer's disease in vivo, Neurovascular Interactions: Mechanisms, Imaging, Therapeutics, Multidimensional mapping of vulnerable cell types in humanized Alzheimer's disease mouse models, Machine Learning Approaches for Behavioral Phenotyping of Humanized Knock-in Models of Alzheimer's Disease, Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
OpenAlex ID: W7160389926