Samenvatting

Objective: Epileptic spikes and seizures seem present early in the disease process of Alzheimer's disease (AD). However, it is unclear how soluble and insoluble amyloid beta (Aβ) and tau proteins affect seizure development in vivo. We aim to contribute to this field by assessing the vulnerability to 6 Hz corneal kindling of young female mice from two well-characterized transgenic AD models and by testing their responsiveness to selected antiseizure drugs (ASDs). Methods: We used 7-week-old triple transgenic (3xTg) mice that have both amyloid and tau mutations, and amyloid precursor protein Swedish/presenillin 1 dE9 (APP/PS1) mice, bearing only amyloid-related mutations. We assessed the absence of plaques via immunohistochemistry and analyzed the concentrations of both soluble and insoluble forms of Aβ1–42 and total tau (t-tau) in brain hippocampal and prefrontal cortical tissue. Seven-week-old mice of the different genotypes were subjected to the 6 Hz corneal kindling model. After kindling acquisition, we tested the anticonvulsant effects of three marketed ASDs (levetiracetam, brivaracetam, and lamotrigine) in fully kindled mice. Results: No Aβ plaques were present in either genotype. Soluble Aβ1–42 levels were increased in both AD genotypes, whereas insoluble Aβ1–42 concentrations were only elevated in APP/PS1 mice compared with their respective controls. Soluble and insoluble forms of t-tau were increased in 3xTg mice only. 3xTg and APP/PS1 mice displayed more severe seizures induced by 6 Hz corneal kindling from the first stimulation onward and were more rapidly kindled compared with control mice. In fully kindled AD mice, ASDs had less-pronounced anticonvulsive effects compared with controls. Significance: Mutations increasing Aβ only or both Aβ and tau in the brain enhance susceptibility for seizures and kindling in mice. The effect of ASDs on seizures measured by the Racine scale is less pronounced in both investigated AD models and suggests that seizures of young AD mice are more difficult to treat.

Originele taal-2English
Pagina's2703-2715
Aantal pagina's13
DOI's
StatusPublished - okt 2022
EvenementInternational League Against Epilepsy - Genève, Switzerland
Duur: 9 jul 202213 jul 2022

Conference

ConferenceInternational League Against Epilepsy
Land/RegioSwitzerland
StadGenève
Periode9/07/2213/07/22

Bibliografische nota

Funding Information:
We thank UCB for providing levetiracetam and brivaracetam. We kindly thank Marie‐Laure Custers, Gino De Smet, Anke De Smet, Niel Ravyts, Chloë Van Cauwenberghe, Jana Van der Cruyssen, and Lore Winters for their assistance with the experiments and Wilfried Cools for his help with the statistical analysis. This work was supported by grants of the FWO Research Foundation ‐ Flanders (11E4819N and G040419N), Wetenschappelijk Fonds Willy Gepts of Vrije Universiteit Brussel, and the National Institutes of Health (KL2TR002317 and R01AG067788).

Funding Information:
We thank UCB for providing levetiracetam and brivaracetam. We kindly thank Marie-Laure Custers, Gino De Smet, Anke De Smet, Niel Ravyts, Chloë Van Cauwenberghe, Jana Van der Cruyssen, and Lore Winters for their assistance with the experiments and Wilfried Cools for his help with the statistical analysis. This work was supported by grants of the FWO Research Foundation - Flanders (11E4819N and G040419N), Wetenschappelijk Fonds Willy Gepts of Vrije Universiteit Brussel, and the National Institutes of Health (KL2TR002317 and R01AG067788).

Publisher Copyright:
© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

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