Temporal lobe epilepsy represents a major cause of drug-resistant epilepsy. Cognitive impairment is a frequent comorbidity, but the mechanisms are not fully elucidated. We hypothesized that the cognitive impairment in drug-resistant temporal lobe epilepsy could be due to perturbations of amyloid and tau signalling pathways related to activation of stress kinases, similar to those observed in Alzheimer's disease. We examined these pathways, as well as amyloid-β and tau pathologies in the hippocampus and temporal lobe cortex of drug-resistant temporal lobe epilepsy patients who underwent temporal lobe resection (n = 19), in comparison with age- and region-matched samples from neurologically normal autopsy cases (n = 22). Post-mortem temporal cortex samples from Alzheimer's disease patients (n = 9) were used as positive controls to validate many of the neurodegeneration-related antibodies. Western blot and immunohistochemical analysis of tissue from temporal lobe epilepsy cases revealed increased phosphorylation of full-length amyloid precursor protein and its associated neurotoxic cleavage product amyloid-β*56. Pathological phosphorylation of two distinct tau species was also increased in both regions, but increases in amyloid-β1-42 peptide, the main component of amyloid plaques, were restricted to the hippocampus. Furthermore, several major stress kinases involved in the development of Alzheimer's disease pathology were significantly activated in temporal lobe epilepsy brain samples, including the c-Jun N-terminal kinase and the protein kinase R-like endoplasmic reticulum kinase. In temporal lobe epilepsy cases, hippocampal levels of phosphorylated amyloid precursor protein, its pro-amyloidogenic processing enzyme beta-site amyloid precursor protein cleaving enzyme 1, and both total and hyperphosphorylated tau expression, correlated with impaired preoperative executive function. Our study suggests that neurodegenerative and stress-related processes common to those observed in Alzheimer's disease may contribute to cognitive impairment in drug-resistant temporal lobe epilepsy. In particular, we identified several stress pathways that may represent potential novel therapeutic targets.

中文翻译：

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与颞叶癫痫的认知缺陷相关的阿尔茨海默氏样淀粉样蛋白和tau改变。

颞叶癫痫是耐药性癫痫的主要原因。认知障碍是一种常见的合并症，但其机制尚未完全阐明。我们假设耐药性颞叶癫痫的认知障碍可能是由于与应激激酶激活相关的淀粉样蛋白和tau信号通路的扰动引起的，类似于在阿尔茨海默氏病中观察到的情况。我们比较了年龄和区域匹配的样本，比较了进行颞叶切除的耐药性颞叶癫痫患者（n = 19）的海马和颞叶皮层的这些途径以及淀粉样蛋白β和tau病理来自神经学上正常的尸检病例（n = 22）。阿尔茨海默氏病的尸体颞皮样品 s病患者（n = 9）被用作阳性对照，以验证许多神经退行性疾病相关抗体。颞叶癫痫病例组织的蛋白质印迹和免疫组织化学分析显示，全长淀粉样蛋白前体蛋白及其相关的神经毒性裂解产物淀粉样蛋白-β* 56的磷酸化增加。两个不同的tau物种的病理磷酸化在两个区域也都增加，但是淀粉样蛋白斑块的主要成分淀粉样蛋白β1-42肽的增加仅限于海马体。此外，在颞叶癫痫脑样本中，几种与阿尔茨海默氏病病理发展有关的主要应激激酶被显着激活，包括c-Jun N端激酶和蛋白激酶R样内质网激酶。在颞叶癫痫病例中，海马水平的磷酸化淀粉样蛋白前体蛋白，其促淀粉样生成酶β位淀粉样蛋白前体蛋白裂解酶1以及总和过度磷酸化的tau表达均与术前执行功能受损有关。我们的研究表明，与阿尔茨海默氏病中常见的神经退行性过程和与压力相关的过程可能导致耐药性颞叶癫痫的认知功能障碍。特别是，我们确定了几种可能代表潜在的新型治疗靶点的应激途径。与术前执行功能受损有关。我们的研究表明，与阿尔茨海默氏病中常见的神经退行性过程和与压力相关的过程可能导致耐药性颞叶癫痫的认知功能障碍。特别是，我们确定了几种可能代表潜在的新型治疗靶点的应激途径。与术前执行功能受损有关。我们的研究表明，与阿尔茨海默氏病中常见的神经退行性过程和与压力相关的过程可能导致耐药性颞叶癫痫的认知功能障碍。特别是，我们确定了几种可能代表潜在的新型治疗靶点的应激途径。