Kavli Affiliate: Mark Ellisman
| Authors: Zhaoqi Yan, Andrew S Mendiola, Kelli Lauderdale, Keun-Young Kim, Yu Yong, Kun Leng, Eric A Bushong, Renaud Schuck, Anke Meyer-Franke, Ayushi Agrawal, Michela Traglia, Natalie Gill, Reuben Thomas, Jonah N Keller, Nikolaos Karvelas, Miguel F Vasquez, Daniel C Ballard, Matthew Madany, Jeffrey Simms, Brandon Guo, Reshmi Tognatta, Maria del Pilar S Alzamora, Rosa Meza-Acevedo, Belinda Cabriga, Kellie N Pierson, Lida Kourita, Kayoung Han, Jae K Ryu, Bruce L Miller, Fanny Elahi, Mark H Ellisman, Jorge J Palop and Katerina Akassoglou
| Summary:
Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimer’s disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand–receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimer’s disease and related conditions. There is a companion manuscript submitted to bioRxiv (Lauderdale et al., 2026)