Seizure-induced enhancement of synaptic signaling regulating tau transmissibility in Alzheimer's Disease

Abstract Alzheimer’s Disease (AD) neuropathology is largely driven by two pathological AD proteins, tau, and ß-amyloid (Aß), both of which induce neuronal hyperexcitability and are thought to play a role in the high comorbidity between AD and epilepsy. Tau load and its regional brain distribution correlate more closely with cognitive decline than amyloid plaque deposition in both AD and epilepsy patients, making tau an attractive target for disease modification in both conditions. AD patients have an increased incidence of epilepsy compared to non-AD patients, and we recently showed that kindled seizures can exacerbate amyloid pathology, mediated by the mammalian target of rapamycin complex 1 (mTORC1) activation in an AD mouse model. To address how neuronal hyperactivity can increase AD pathology, we propose to use a tau seeding approach using two novel AD mice models to determine the effects of later seizures on the spatiotemporal accumulation of pathologic tau. We will also test the hypothesis that tau transmissibility in AD occurs through synaptic activation by adapting a method to permanently label cells activated by kindled seizures following tau seeding. This will allow us to measure the levels and spatial and temporal distribution of tau and AD pathology throughout the entire brain, as well as gene and protein expression at single neuron level. We will also utilize human brain tissue from AD patients with and without a seizure history, and controls, to validate molecular changes observed in the mouse models. Finally, given our prior observations regarding the therapeutic effects of rapamycin, and the hypothesis that tau accumulation and transmission is accelerated by seizures, we will use the two tau seeding mouse models to assess the therapeutic efficacy of post-seizure chronic treatment with the mTORC1 inhibitor rapamycin or the antiseizure drug levetiracetam in attenuating AD progression.