Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms

Abstract

Tau is a microtubule-associated protein known to bind and promote assembly of microtubules in neurons under physiological conditions. However, under pathological conditions, aggregation of hyperphosphorylated tau causes neuronal toxicity, neurodegeneration, and resulting tauopathies like Alzheimer's disease (AD). Clinically, patients with tauopathies present with either dementia, movement disorders, or a combination of both. The deposition of hyperphosphorylated tau in the brain is also associated with epilepsy and network hyperexcitability in a variety of neurological diseases. Furthermore, pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects. Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer's and epilepsy models. However, it remains unclear whether tauopathy and epilepsy comorbidities are mediated by convergent mechanisms occurring upstream of epileptogenesis and tau aggregation, by feedforward mechanisms between the two, or simply by coincident processes. In this review, we investigate the relationship between tauopathies and seizure disorders, including temporal lobe epilepsy (TLE), post-traumatic epilepsy (PTE), autism spectrum disorder (ASD), Dravet syndrome, Nodding syndrome, Niemann-Pick type C disease (NPC), Lafora disease, focal cortical dysplasia, and tuberous sclerosis complex. We also explore potential mechanisms implicating the role of tau kinases and phosphatases as well as the mammalian target of rapamycin (mTOR) in the promotion of co-pathology. Understanding the role of these co-pathologies could lead to new insights and therapies targeting both epileptogenic mechanisms and cognitive decline.

Keywords: cognitive decline; epilepsy; hyperexcitability; hyperphosphorylation of tau; mTOR; tau.

FIGURE 1

Cascade of events in development of seizures and tau pathology. Endogenous tau has an enabling function in the development of seizure activity following disease onset or traumatic insult. Network hyperexcitability in turn leads to cognitive decline and the activation of mechanisms involving mTOR and tau kinases and phosphatases, resulting in abnormal phosphorylation of tau. Overactivation of these cell signaling pathways increases susceptibility to pathological tau hyperphosphorylation and aggregation, which may also contribute to epilepsy-associated cognitive decline. GSK-3β, glycogen synthase kinase-3β; CDK5, cyclin-dependent kinase 5; PP2A, protein phosphatase 2A; mTOR, mammalian target of rapamycin; p-tau, abnormally phosphorylated tau. Created with BioRender.com.

FIGURE 2

Simplified diagram of activated kinase signaling cascades in epilepsy. Epileptic activity leads to the activation of tau kinases, GSK-3β and CDK5, as well as mTOR. Dashed-line arrows indicate indirect activation of mTOR by GSK-3β through the mTOR complex 1 and of CDK5 by mTOR through amyloid-β aggregation and calpain activation. The downstream targets of mTOR activation involve the activation of additional tau kinases, p70S6K1 and eIF4E. GSK-3β, glycogen synthase kinase-3β; mTOR, mammalian target of rapamycin; CDK5, cyclin-dependent kinase 5; S6K1, ribosomal protein S6 kinase 1; 4EBP1, 4E binding protein 1; p70S6K1, phosphorylated S6K1; eIF4E, eukaryotic translation initiation factor 4E; p-tau, abnormally phosphorylated tau. Created with BioRender.com.

FIGURE 3

Interplay of endogenous tau, mTOR, and autophagy in epilepsy. (A) Under normal physiological conditions (blue), endogenous tau positively regulates mTOR activity via PTEN inhibition, and mTOR in turn negatively regulates autophagy mechanisms that contribute to the clearance of tau and p-tau. (B) In hyperexcitability states found in pathophysiological conditions such as tuberous sclerosis complex and Niemann-Pick type C disease (red), overactivation of mTOR due to increased PTEN inhibition causes excess inhibition of autophagy, resulting in reduced clearance of tau species. Elevated levels of normal tau in turn exacerbate epileptic activity and mTOR disinhibition. PTEN, phosphatase and tensin homolog deleted chromosome 10; mTOR, mammalian target of rapamycin; p-tau, phosphorylated tau. Created with BioRender.com.