Hyperactive neuronal networks facilitate tau spread in an Alzheimer's disease mouse model.

Pathological tau spreads throughout the brain along neuronal connections in Alzheimer's disease (AD), but the mechanisms that underlie this process are poorly understood. Given the high incidence and deleterious consequences of epileptiform activity in AD, we hypothesized neuronal hyperactivity and seizures are key factors in tau spread. To examine these interactions, we created a novel mouse model involving the cross of targeted recombination in active populations (TRAP) mice and the 5 times familial AD (5XFAD; 5X-TRAP) model allowing for the permanent fluorescent labelling of neuronal activity. To establish a causal role of seizures in tau spread, we seeded mice with human AD brain-derived tau lysate and induced seizures with pentylenetetrazol (PTZ) kindling. Comprehensive brain mapping of tau pathology and neuronal activity revealed that basal hyperactivity in 5X-TRAP mice was associated with increased tau spread, which was exacerbated by seizure induction through activated networks and correlated with memory deficits. Computational modeling revealed that anterograde tau spread was elevated in 5X-TRAP mice and that regional neuronal activity was predictive of tau spread to that brain region. On a cellular level, we found that in both saline and PTZ-treated 5X-TRAP mice, hyperactive neurons disproportionately contributed to the spread of tau. Further, we found that Synaptogyrin-3, a synaptic vesicle protein that interacts with tau, was increased following PTZ kindling in 5X-TRAP mice, possibly indicative of a synaptic mechanism underlying seizure-exacerbated tau spread. Importantly, postmortem AD brain tissue from patients with a history of seizures showed increased tau pathology in patterns indicative of increased spread and increased Synaptogyrin-3 levels compared to those without seizures. Overall, our study identifies neuronal hyperactivity and seizures as key factors underlying the pathobiological and cognitive progression of AD. Therapies targeting these factors should be tested clinically to slow tau spread and AD progression.