Donald W, Reynolds Department of Geriatrics, University of Arkansas College of Medicine, Little Rock, AR 72205, USA.
Acta Neuropathol Commun. 2013 Jul 29;1:41. doi: 10.1186/2051-5960-1-41.
Precocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE ϵ4,4 carriers is well known, but not the ways in which other APOE allelic combinations influence this outcome. Frozen and paraffin-embedded tissue samples resected from superior temporal lobes of 92 patients undergoing temporal lobectomies as a treatment for medication-resistant temporal lobe epilepsy were used in this study. To determine if epilepsy-related changes reflect those in another neurological condition, analogous tissue samples harvested from 10 autopsy-verified Alzheimer brains, and from 10 neurologically and neuropathologically normal control patients were analyzed using immunofluorescence histochemistry, western immunoblot, and real-time PCR to determine genotype effects on neuronal number and size, neuronal and glial expressions of amyloid β (Aβ) precursor protein (βAPP), Aβ, apolipoprotein E (ApoE), S100B, interleukin-1α and β, and α and β secretases; and on markers of neuronal stress, including DNA/RNA damage and caspase 3 expression.
Allelic combinations of APOE influenced each epilepsy-related neuronal and glial response measured as well as neuropathological change. APOE ϵ3,3 conferred greatest neuronal resilience denoted as greatest production of the acute phase proteins and low neuronal stress as assessed by DNA/RNA damage and caspase-3 expression. Among patients having an APOE ϵ2 allele, none had Aβ plaques; their neuronal sizes, like those with APOE ϵ3,3 genotype were larger than those with other genotypes. APOE ϵ4,4 conferred the weakest neuronal resilience in epilepsy as well as in Alzheimer patients, but there were no APOE genotype-dependent differences in these parameters in neurologically normal patients.
Our findings provide evidence that the strength of the neuronal stress response is more related to patient APOE genotype than to either the etiology of the stress or to the age of the patient, suggesting that APOE genotyping may be a useful tool in treatment decisions.
众所周知，在癫痫患者中，尤其是 APOE ϵ4,4 携带者中，阿尔茨海默病样神经病理变化会过早发展。但其他 APOE 等位基因组合如何影响这一结果尚不清楚。本研究使用了从 92 名接受颞叶切除术治疗药物难治性颞叶癫痫的患者的颞叶切除术中切除的冷冻和石蜡包埋组织样本。为了确定癫痫相关变化是否反映了另一种神经状况，我们还分析了从 10 例经尸检证实的阿尔茨海默病大脑和 10 例神经和神经病理学正常的对照患者中获得的类似组织样本，采用免疫荧光组织化学、western 免疫印迹和实时 PCR 确定基因型对神经元数量和大小、神经元和神经胶质淀粉样前体蛋白（βAPP）、Aβ、载脂蛋白 E（ApoE）、S100B、白细胞介素-1α 和 β 以及 α 和 β 分泌酶的表达以及神经元应激的标志物，包括 DNA/RNA 损伤和半胱天冬酶 3 的表达。
APOE 的等位基因组合影响了每种与癫痫相关的神经元和神经胶质反应以及神经病理学变化。APOE ϵ3,3 赋予最大的神经元弹性，表现为急性相蛋白产量最高，DNA/RNA 损伤和 caspase-3 表达最低的神经元应激。在携带 APOE ϵ2 等位基因的患者中，没有 Aβ 斑块；其神经元大小与 APOE ϵ3,3 基因型相似，大于其他基因型。APOE ϵ4,4 在癫痫患者以及阿尔茨海默病患者中赋予最弱的神经元弹性，但在神经正常的患者中，这些参数与 APOE 基因型无关。
我们的发现提供了证据，表明神经元应激反应的强度与患者的 APOE 基因型更相关，而与应激的病因或患者的年龄无关，这表明 APOE 基因分型可能是治疗决策的有用工具。
