Abstracts

Rationale: Neurologic disorders are among the most significant health challenges facing society today. Although different neurologic disorders are often thought to be distinct from one another, evidence suggests similar processes may contribute to pathology in different diseases, including epilepsy and Alzheimer’s Disease. Previous studies suggest that common disease mechanisms link the development of epilepsy and tauopathy. The purpose of this study is to better define this relationship in an effort to define new potential therapeutic avenues to slow disease progress. Methods: The pilocarpine-induced status epilepticus (SE) model of temporal lobe epilepsy was used to explore the effect of severe seizures on tau pathology in 7 week old C57BL6 mice. SE was induced via intraperitoneal injection of pilocarpine (280-285 mg/kg). The mice were monitored by observation for 2 hours after treatment and behavioral seizures were ranked according a modified Racine scale. Brains were collected from mice at 6 hours, 24 hours, or 12 weeks after induced SE (n=5-9 at each timepoint). Hippocampal homogenates were analyzed via Western blot to look for changes in tau phosphorylation or activity of three major regulators of tau phosphorylation: GSK3β, cdk5, and PP2A. Immunohistochemistry was performed on PFA fixed slices. Tissue sections (40 µm) were stained for phosphorylated/total tau, GSK3β, cdk5, PP2A, and cell specific markers (NeuN and GFAP). Results: The results of this study show an nominal increase (point estimate) in the expression of the C subunit of PP2A and the cdk5 activator p35, and a significant decrease in expression of GSK3β at 24 hours post-SE (p<0.01). Tau phosphorylation was unchanged at 6 hours but showed a nominal increase at 24 hours post-SE. Additional trials are required to increase statistical power. However, expression of pT231 tau at six hours post-SE was positively correlated with seizure burden during the SE induction (R2=0.805; p<0.05) and phosphorylation of GSK3β at Y216 was negatively correlated with seizure burden (R2=0.79; p<0.05). Conclusions: The present results suggest an initial increase in phosphatase activity after SE. This potential compensatory mechanism is short lived, however, and tau phosphorylation is elevated in mice with a high seizure burden during SE and begins to rise overall by 24 hours-post SE. The rise in tau phosphorylation may be driven primarily by increased activity of cdk5. Funding: NIGMS 1T32GM118292, NINDS 1R01NS902552 NINDS 1R01NS091329, DOD AZ140097, TL1TR001997