Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
Department of Neurology, Universitair Ziekenhuis Brussel, Jette, Belgium.
Epilepsia. 2022 Oct;63(10):2703-2715. doi: 10.1111/epi.17355. Epub 2022 Aug 2.
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).
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 Aβ 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.
No Aβ plaques were present in either genotype. Soluble Aβ levels were increased in both AD genotypes, whereas insoluble Aβ 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.
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.
阿尔茨海默病（AD）疾病过程早期似乎就存在癫痫棘波和癫痫发作。然而，可溶性和不溶性淀粉样β（Aβ）和tau 蛋白如何影响体内癫痫发作的发展尚不清楚。我们旨在通过评估两种经过充分表征的 AD 转基因模型的年轻雌性小鼠对 6Hz 角膜点燃的易感性，并测试它们对选定的抗癫痫药物（ASD）的反应，为该领域做出贡献。
我们使用了 7 周龄的三转基因（3xTg）小鼠，该小鼠既有淀粉样蛋白和 tau 突变，又有淀粉样前体蛋白瑞典/早老素 1 dE9（APP/PS1）小鼠，仅具有与淀粉样蛋白相关的突变。我们通过免疫组织化学评估斑块的缺失，并分析大脑海马和前额皮质组织中可溶性和不溶性 Aβ 以及总 tau（t-tau）的浓度。不同基因型的 7 周龄小鼠接受 6Hz 角膜点燃模型。在获得点燃后，我们在完全点燃的小鼠中测试了三种市售 ASD（左乙拉西坦、布瓦西坦和拉莫三嗪）的抗惊厥作用。
两种基因型均未出现 Aβ 斑块。可溶性 Aβ 水平在两种 AD 基因型中均升高，而不溶性 Aβ 浓度仅在 APP/PS1 小鼠中与各自的对照相比升高。3xTg 小鼠的可溶性和不溶性 t-tau 均升高。3xTg 和 APP/PS1 小鼠与对照小鼠相比，从第一次刺激开始，由 6Hz 角膜点燃引起的癫痫发作更严重，并且更快地被点燃。在完全点燃的 AD 小鼠中，与对照相比，ASD 的抗惊厥作用不那么明显。
增加大脑中 Aβ 的突变或 Aβ 和 tau 的突变均增强了小鼠对癫痫发作和点燃的易感性。Racine 量表测量的 ASD 对癫痫发作的影响在两种研究的 AD 模型中均不明显，这表明年轻 AD 小鼠的癫痫发作更难治疗。
