Resilience to neuronal hyperactivity and restoration of the neuroimmune interactome and decision-making by blocking fibrin in a model of Alzheimer's disease.

UNLABELLED: 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. HIGHLIGHTS: Vascular-microglia axis drives neuronal hyperactivityFibrin inflammatory activity disrupts the microglia-neuron interactomeMicroglia activation by fibrin impairs decision-making in AD miceSynaptic dysfunction and immune biomarkers correlate with CSF fibrinogen in AD patients.