Patients with Alzheimer's disease (AD) experience seizures at higher rates than the general population of that age, suggesting an underexplored role of hyperexcitability in AD. Genetic variants in presenilin (PSEN) 1 and 2 genes lead to autosomal dominant early-onset AD (ADAD); patients with PSEN gene variants also report seizures. Pharmacological control of seizures in AD may be disease-modifying. Preclinical efficacy of FDA-approved antiseizure drugs (ASDs) is well defined in young adult rodents; however, the efficacy of ASDs in aged rodents with chronic seizures is less clear. The mechanism by which ADAD genes lead to AD remains unclear, and even less studied is the pathogenesis of epilepsy in AD. PSEN variants generally all result in a biochemical loss of function (De Strooper, 2007). We herein determined whether well-established models of acute and chronic seizure could be used to explore the relationship between AD genes and seizures through investigating whether loss of normal PSEN2 function age-dependently influenced susceptibility to seizures and/or corneal kindling acquisition. PSEN2 knockout (KO) and age-matched wild-type (WT) mice were screened from 2- to 10-months-old to establish age-dependent focal seizure threshold. Additionally, PSEN2 KO and WT mice aged 2- and 8-months-old underwent corneal kindling such that mice were aged 3- and 9-months old at the beginning of ASD efficacy testing. We then defined the dose-dependent efficacy of mechanistically distinct ASDs on kindled seizures of young versus aged mice to better understand the applicability of corneal kindling to real-world use for geriatric patients. PSEN2 KO mice demonstrated early-life reductions in seizure threshold. However, kindling acquisition was delayed in 2-month-old PSEN2 KO versus WT mice. Young male WT mice took 24.3 ± 1.3 (S.E.M.) stimulations to achieve kindling criterion, whereas age-matched PSEN2 KO male mice took 41.2 ± 1.1 stimulations (p < .0001). The rate of kindling acquisition of 8-month-old mice was no longer different from WT. This study demonstrates that loss of normal PSEN2 function is associated with age-dependent changes in the in vivo susceptibility to acute seizures and kindling. Loss of normal PSEN2 function may be an underexplored molecular contributor to seizures. The use of validated models of chronic seizures in aged rodents may uncover age-related changes in susceptibility to epileptogenesis and/or ASD efficacy in mice with AD-associated genotypes, which may benefit the management of seizures in AD.

中文翻译：

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早老素2的丢失依赖于年龄，会改变其对急性癫痫发作和点燃习性的敏感性。

阿尔茨海默氏病（AD）患者的癫痫发作率高于该年龄段的普通人群，这表明过度兴奋性在AD中的作用尚未得到充分开发。早老素（PSEN）1和2基因的遗传变异导致常染色体显性遗传的早发性AD（ADAD）；PSEN基因变异的患者也报告有癫痫发作。AD癫痫发作的药理控制可能会缓解疾病。FDA批准的抗癫痫药物（ASD）的临床前疗效在成年啮齿类动物中已有很好的定义。然而，ASDs在患有慢性癫痫的老年啮齿动物中的功效尚不清楚。ADAD基因导致AD的机制仍不清楚，甚至很少研究是AD癫痫的发病机理。PSEN变异通常都会导致生化功能丧失（De Strooper，2007）。我们在这里通过调查正常PSEN2功能的丧失是否取决于年龄是否影响癫痫发作和/或角膜点燃获取的易感性，来确定是否可以使用已建立的急性和慢性癫痫发作模型来探讨AD基因与癫痫发作之间的关系。从2到10个月大的年龄筛选PSEN2基因敲除（KO）和年龄匹配的野生型（WT）小鼠，以建立年龄依赖性局灶性癫痫发作阈值。此外，对2个月和8个月大的PSEN2 KO和WT小鼠进行了角膜点燃，使得小鼠在ASD功效测试开始时分别为3个月和9个月大。然后，我们定义了机械上不同的ASD对年轻与老年小鼠的点燃性癫痫发作的剂量依赖性功效，以更好地了解角膜点燃对老年患者实际应用的适用性。PSEN2 KO小鼠表现出癫痫发作阈值的早期降低。但是，与WT小鼠相比，在2个月大的PSEN2 KO中，点燃获取延迟了。年轻的雄性WT小鼠接受24.3±1.3（SEM）刺激以达到点燃标准，而年龄匹配的PSEN2 KO雄性小鼠接受41.2±1.1刺激（p <.0001）。8个月大小鼠的点燃获取率与WT不再相同。这项研究表明，正常PSEN2功能的丧失与体内对急性发作和点燃的敏感性的年龄依赖性变化有关。正常PSEN2功能的丧失可能是癫痫发作的分子探索不足。在老年啮齿动物中使用经过验证的慢性癫痫发作模型可能会发现与AD相关基因型的小鼠对癫痫发生敏感性和/或ASD功效的年龄相关变化，