APOE4 Promotes Tonic-Clonic Seizures, an Effect Modified by Familial Alzheimer's Disease Mutations.
APOE4 Promotes Tonic-Clonic Seizures, an Effect Modified by Familial Alzheimer's Disease Mutations.
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APOE4促进了隆隆声癫痫发作，这种作用是由家族性阿尔茨海默氏病突变所改变的。
DOI：
10.3389/fcell.2021.656521
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发表时间：
2021
影响因子：
5.5
通讯作者：
Tai LM
中科院分区：
文献类型：
--
作者：
Lamoureux L;Marottoli FM;Tseng KY;Tai LM
癫痫发作是阿尔茨海默病（AD）患者的常见症状，通常归因于高水平的淀粉样蛋白β（Aβ）。然而，AD疾病的危险因素在多大程度上调节癫痫发作活动在老龄化和AD相关的背景尚不清楚。APOE 4是AD的最大遗传风险因子，与癫痫发作相关，与AD和Aβ无关。本研究的目的是评估APOE基因型在体内高Aβ水平存在和不存在时调节癫痫发作的作用。为了实现这一目标，我们使用了EFAD小鼠，这些小鼠在不存在（EFAD−）或存在（EFAD+）导致Aβ过度产生的家族性AD突变的情况下表达人APOE 3或APOE 4。当在换笼日进行定量时，我们发现与APOE 3不同，APOE 4与强直阵挛性癫痫发作相关。有趣的是，与E4 FAD −小鼠相比，E4 FAD+小鼠的强直-阵挛性癫痫发作较低。束缚处理和听觉刺激未能重现表达APOE 4的EFAD小鼠的强直-阵挛表型。然而，在使用戊四唑进行化学诱导后，与APOE 3相比，APOE 4的强直阵挛性癫痫发作发生率更高。有趣的是，强直阵挛表型的癫痫发作分布在FAD突变的患者中更高。这些数据支持APOE 4与体内更高的强直-阵挛性发作相关，并且FAD突变以范式依赖性方式影响强直-阵挛性发作。
Seizures are emerging as a common symptom in Alzheimer’s disease (AD) patients, often attributed to high levels of amyloid β (Aβ). However, the extent that AD disease risk factors modulate seizure activity in aging and AD-relevant contexts is unclear. APOE4 is the greatest genetic risk factor for AD and has been linked to seizures independent of AD and Aβ. The goal of the present study was to evaluate the role of APOE genotype in modulating seizures in the absence and presence of high Aβ levels in vivo. To achieve this goal, we utilized EFAD mice, which express human APOE3 or APOE4 in the absence (EFAD−) or presence (EFAD+) of familial AD mutations that result in Aβ overproduction. When quantified during cage change day, we found that unlike APOE3, APOE4 is associated with tonic-clonic seizures. Interestingly, there were lower tonic-clonic seizures in E4FAD+ mice compared to E4FAD− mice. Restraint handing and auditory stimuli failed to recapitulate the tonic-clonic phenotype in EFAD mice that express APOE4. However, after chemical-induction with pentylenetetrazole, there was a higher incidence of tonic-clonic seizures with APOE4 compared to APOE3. Interestingly, the distribution of seizures to the tonic-clonic phenotype was higher with FAD mutations. These data support that APOE4 is associated with higher tonic-clonic seizures in vivo, and that FAD mutations impact tonic-clonic seizures in a paradigm dependent manner.
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影响因子：
6.1
作者：
Garcia-Cabrero, Ana M.;Guerrero-Lopez, Rosa;Sanchez, Marina P.
通讯作者：
Sanchez, Marina P.
影响因子：
2.7
作者：
Bour, Alexandra;Grootendorst, Jeannette;Mathis, Chantal
通讯作者：
Mathis, Chantal
影响因子：
11.2
作者：
Gouras, GK;Relkin, NR;Gandy, S
通讯作者：
Gandy, S
影响因子：
5.6
作者：
Angel, Ariel;Volkman, Rotem;Offen, Daniel
通讯作者：
Offen, Daniel
影响因子：
5.5
作者：
Friedman D;Honig LS;Scarmeas N
通讯作者：
Scarmeas N