Abstract
Hyperphosphorylation of the microtubule-associated protein tau and its resultant aggregation into neurofibrillary tangles (NFT) is a pathological characteristic of neurodegenerative disorders known as tauopathies. Tau is a neuronal protein involved in the stabilization of microtubule structures of the axon and the aberrant phosphorylation of tau is associated with several neurotoxic effects. The discovery of tau pathology and aggregates in the cortex of Temporal lobe epilepsy (TLE) patients has focused interest on hyperphosphorylation of tau as a potential mechanism contributing to increased states of hyperexcitability and cognitive decline. Previous studies using animal models of status epilepticus and tissue from patients with TLE have shown increased tau phosphorylation in the brain following acute seizures and during epilepsy, with tau phosphorylation correlating with cognitive deficits in patients. Suggesting a functional role of tau during epilepsy, studies in tau-deficient and tau-overexpressing mice have demonstrated a causal role of tau during seizure generation. Previous studies, analyzing the impact of seizures on tau hyperphosphorylation, have mainly used animal models of acute seizures. These models, however, do not replicate all aspects of chronic epilepsy. In this study, we investigated the effects of acute seizures (status epilepticus) and chronic epilepsy upon the expression and phosphorylation of tau using the intra-amygdala kainic acid (KA)-induced status epilepticus mouse model. Status epilepticus resulted in an immediate increase in total tau levels in the hippocampus, in particular, the dentate gyrus, and phosphorylation of the AT8 epitope (Ser202, Thr205), with phosphorylated tau mainly localizing to the mossy fibers of the dentate gyrus. During epilepsy, abnormal phosphorylation of tau was detected again at the AT8 epitope with lower total tau levels in the CA3 and CA1 subfields of the hippocampus. Chronic epilepsy in mice also resulted in a strong localization of AT8 phospho-tau to microglia, indicating a distinct pattern of tau hyperphosphorylation during chronic epilepsy compared to status epilepticus. Our results reaffirm previous observations of tau phosphorylation post-status epilepticus, but also elaborate on tau alterations in epileptic mice which more faithfully mimic TLE. Our results confirm seizures affect tau hyperphosphorylation, however, suggest epitope-specific phosphorylation of tau and differences in cell-specific localization according to disease progression.
Highlights
Tauopathies are a diverse group of neurodegenerative disorders characterized by misfolded, aggregated and aberrant forms of the microtubule-associated protein tau (Götz et al, 2019)
Tau can be targeted by numerous kinases in vivo, this is limited to a small group of well-characterized kinases which includes Glycogen synthase kinase-3β (GSK-3β), Cyclindependent kinase 5 (CDK5) and Microtubule-affinity-regulating kinase (MARK; Martin et al, 2013b)
Increases in tau phosphorylation at the AT8 epitope were present at 1 h, 4 h and 8 h when not corrected to total tau levels [Ctrl vs. 1 h post-status epilepticus: 2.954 ± 0.6304, p = 0.01; Ctrl vs. 4 h post-status epilepticus: 3.111 ± 0.3991, p = 0.008; Ctrl vs. 8 h: 3.401 ± 0.4129, p = 0.003; ANOVA post hoc Fisher’s test; Supplementary Figure S1B]
Summary
Tauopathies are a diverse group of neurodegenerative disorders characterized by misfolded, aggregated and aberrant forms of the microtubule-associated protein tau (Götz et al, 2019). Tau can be targeted by numerous kinases in vivo, this is limited to a small group of well-characterized kinases which includes Glycogen synthase kinase-3β (GSK-3β), Cyclindependent kinase 5 (CDK5) and Microtubule-affinity-regulating kinase (MARK; Martin et al, 2013b). These kinases work in tandem with a group of phosphatases [Protein phosphatase-1, -2 and -5 (PP1/2/5)] to curate the modifications and thereby the function of tau in the cell (Martin et al, 2013a). The primary mechanism by which these aberrant modifications induce neurodegeneration in cells is heavily debated and can be loosely divided into two groups including a loss-of-function, where hyperphosphorylation of tau blocks its interaction and stabilization of microtubule structures possibly impacting on axonal transport and synaptic transmission (Feinstein and Wilson, 2005), or a toxic-gain-of function where hyperphosphorylation of tau drives aberrant interactions such as disruption of the trafficking and anchoring of receptors in dendritic compartments or negatively affecting mitochondrial function (Hoover et al, 2010; Lasagna-Reeves et al, 2011)
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