Imagine your brain is like a bustling city, and tau is the dedicated construction worker building and maintaining the roads (microtubules) that keep everything running smoothly. But sometimes, tau goes rogue and starts causing chaos instead – leading to neurodegenerative diseases known as tauopathies. And it turns out, these tauopathies have a connection to seizures too! Researchers are investigating how hyperphosphorylated tau, the troublemaker version of tau, can contribute to epilepsy and network hyperexcitability in various neurological disorders. By understanding the underlying mechanisms and interactions between epileptic episodes and tau aggregation, scientists hope to develop new treatments that address both cognitive decline and seizure activity. This review article delves into the intriguing link between tauopathies and seizure disorders, such as Alzheimer’s disease, autism spectrum disorder, and tuberous sclerosis complex. It explores potential roles of tau kinases, phosphatases, and the mTOR pathway in driving these co-pathologies. The findings from this research could pave the way for innovative therapies that tackle epilepsy and cognitive impairment simultaneously! So hop on board this exciting investigation and learn more about the fascinating interplay between tau and seizures!

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.

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