Dataset Information

Tau Phosphorylation in a Mouse Model of Temporal Lobe Epilepsy.

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.

SUBMITTER: Alves M

PROVIDER: S-EPMC6861366 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Tau Phosphorylation in a Mouse Model of Temporal Lobe Epilepsy.

Alves Marianna M Kenny Aidan A de Leo Gioacchino G Beamer Edward H EH Engel Tobias T

Frontiers in aging neuroscience 20191112

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 ...[more]

PMID: 31780921

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Project description:Objective:Reproductive dysfunction is a comorbidity that commonly occurs with temporal lobe epilepsy (TLE). Characterization of this comorbidity in various models of TLE in mice will greatly facilitate mechanistic investigations of the relationship between reproductive disorders and seizures initiated in the hippocampus. Here we investigate the impact on female reproductive estrous cyclicity in the intrahippocampal kainic acid mouse model of TLE and demonstrate the utility of using this model for future mechanistic studies. Methods:Kainic acid (KA) or saline vehicle was stereotaxically injected in the right dorsal hippocampus of adult female C57BL/6J mice. Development of epilepsy was assessed by video monitoring for behavioral seizures. Reproductive function was assessed by daily estrous cycle monitoring and ovarian morphology. Estrous cycles were monitored for up to 2 months after injection. Ovarian morphology was examined by histological staining and assessment of follicular and luteal development. Results:We observed spontaneous behavioral seizures in 82% of kainic-acid-treated mice. Irregular estrous cycles developed within 2 months after kainic acid injection. Sixty-seven percent of KA-treated mice showed disrupted estrous cycles, typically characterized by increased estrous cycle length, increased time spent in diestrus (nonfertile stage), and decreased time spent in estrus by 42 days post-KA injection. The estrous cycle disruption, however, was not accompanied by major changes in ovarian morphology or follicular development. KA-treated mice also displayed increased weight gain compared to control mice. Significance:These data indicate that comorbid female irregular estrous cyclicity arises in the intrahippocampal kainic acid mouse model of TLE. This is the first demonstration of disrupted reproductive endocrine function in a mouse model of TLE initially produced by an insult specifically targeted to the hippocampus. This model should thus be useful for basic studies investigating the neural mechanisms driving comorbid reproductive dysfunction in epilepsy in women.

Project description:Temporal lobe epilepsy represents a major cause of drug-resistant epilepsy. Cognitive impairment is a frequent comorbidity, but the mechanisms are not fully elucidated. We hypothesized that the cognitive impairment in drug-resistant temporal lobe epilepsy could be due to perturbations of amyloid and tau signalling pathways related to activation of stress kinases, similar to those observed in Alzheimer's disease. We examined these pathways, as well as amyloid-β and tau pathologies in the hippocampus and temporal lobe cortex of drug-resistant temporal lobe epilepsy patients who underwent temporal lobe resection (n = 19), in comparison with age- and region-matched samples from neurologically normal autopsy cases (n = 22). Post-mortem temporal cortex samples from Alzheimer's disease patients (n = 9) were used as positive controls to validate many of the neurodegeneration-related antibodies. Western blot and immunohistochemical analysis of tissue from temporal lobe epilepsy cases revealed increased phosphorylation of full-length amyloid precursor protein and its associated neurotoxic cleavage product amyloid-β*56. Pathological phosphorylation of two distinct tau species was also increased in both regions, but increases in amyloid-β1-42 peptide, the main component of amyloid plaques, were restricted to the hippocampus. Furthermore, several major stress kinases involved in the development of Alzheimer's disease pathology were significantly activated in temporal lobe epilepsy brain samples, including the c-Jun N-terminal kinase and the protein kinase R-like endoplasmic reticulum kinase. In temporal lobe epilepsy cases, hippocampal levels of phosphorylated amyloid precursor protein, its pro-amyloidogenic processing enzyme beta-site amyloid precursor protein cleaving enzyme 1, and both total and hyperphosphorylated tau expression, correlated with impaired preoperative executive function. Our study suggests that neurodegenerative and stress-related processes common to those observed in Alzheimer's disease may contribute to cognitive impairment in drug-resistant temporal lobe epilepsy. In particular, we identified several stress pathways that may represent potential novel therapeutic targets.

Dataset Information

Tau Phosphorylation in a Mouse Model of Temporal Lobe Epilepsy.

Publications

Tau Phosphorylation in a Mouse Model of Temporal Lobe Epilepsy.

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