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Cited by 54Epilepsy research and treatmentAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Tau phosphorylation in a mouse model of temporal lobe epilepsy.

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Alves, Marianna, Kenny, Aidan, de Leo, Gioacchino, Beamer, Edward H., Engel, Tobias·2019·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2019.00308PMC PMC6861366
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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.

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  • In animal models of temporal lobe epilepsy, tau hyperphosphorylation is observed in the amygdala, hippocampus, and cortex following chemical and electrical amygdala kindling.

    “In animal models of TLE, tau hyperphosphorylation is observed in relevant brain regions, including the amygdala, hippocampus, and cortex, following chemical and electrical amygdala kindling (Jones et al., 2012; Liu et al., 2016; Alves et al., 2019).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Alves et al., 2019

    The Results (page not available) report increased tau phosphorylation in the hippocampus after chemically induced status epilepticus from an intra-amygdala kainic acid injection. The cited paper does not establish tau hyperphosphorylation in the amygdala or cortex, or after electrical amygdala kindling; its mention of cortical injury is not a phosphorylation finding. (LLM, conf=0.88)

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  • GSK-3β inhibitor pretreatment lacks effect on hippocampal p-tau in the intra-amygdala kainic acid-induced status epilepticus mouse model.

    “and the lack of effect on hippocampal p-tau by GSK-3β inhibitor pretreatment in the intra-amygdala kainic acid-induced status epilepticus mouse model (Alves et al., 2019) indicate that GSK-3β is not the only kinase responsible for tau phosphorylation following epileptic activity.”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Alves et al., 2019

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Authors
Alves, M., Kenny, A., de Leo, G., Beamer, E. H., & Engel, T.
Affiliations
Royal College of Surgeons in Ireland (IE)
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2019-11-12
Volume
11
Pages
308-308
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2019.00308
PMC
PMC6861366
OpenAlex
W2989001819
Cited by
54
References
54
Citations by year
2026: 6 · 2025: 13 · 2024: 5 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 4
FWCI
4.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • SHURA (Sheffield Hallam University Research Archive) (Sheffield Hallam University) (submittedVersion)
Funders
  • Health Research Board (HRA-POR-2015-1243)
  • Science Foundation Ireland (17/CDA/4708)
  • H2020 Marie Skłodowska-Curie Actions (753527)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
tau phosphorylation, temporal lobe epilepsy, status epilepticus, kainic acid, neurofibrillary tangles, tauopathy, hippocampus, microglia, chronic epilepsy, seizure-induced neurodegeneration, mouse model

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