Increased transcription of transglutaminase 1 mediates neuronal death in in vitro models of neuronal stress and Aβ1-42-mediated toxicity
Increased transcription of transglutaminase 1 mediates neuronal death in in vitro models of neuronal stress and Aβ1-42-mediated toxicity
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DOI：
10.1016/j.nbd.2020.104849
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发表时间：
2020-07-01
影响因子：
6.1
通讯作者：
Basso, Manuela
中科院分区：
文献类型：
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作者：
Tripathy, Debasmita;Migazzi, Alice;Basso, Manuela
阿尔茨海默病(AD)是导致痴呆症的最常见原因。在疾病的症状前期，淀粉样前体蛋白(APP)的加工会产生有毒的多肽，称为淀粉样β1-42(Aβ1-42)。Aβ1-42生产的下游影响尚未完全揭开.在这里，我们报告了转谷氨酰胺酶1(TG1)在体外AD神经元毒性模型中的作用。在疾病晚期，阿尔茨海默病小鼠模型的海马区和经历应激的初级皮质神经元中TG1增加。沉默TGM1基因足以防止Aβ介导的神经元死亡。相反，它的过度表达促进了细胞死亡。TGM1的上调是由激活蛋白1(AP1)结合位点在转录水平上介导的，当突变时，AP1会阻止TGM1启动子的激活。这些结果表明，TG1作用于Aβ毒性的下游，其应激依赖性的增加使其适合于药物干预。
Alzheimer's disease (AD) is the most common cause of dementia. At the pre-symptomatic phase of the disease, the processing of the amyloid precursor protein (APP) produces toxic peptides, called amyloid-beta 1-42 (A beta 1-42). The downstream effects of A beta 1-42 production are not completely uncovered. Here, we report the involvement of transglutaminase 1 (TG1) in in vitro AD models of neuronal toxicity. TG1 was increased at late stages of the disease in the hippocampus of a mouse model of AD and in primary cortical neurons undergoing stress. Silencing of TGM1 gene was sufficient to prevent A beta-mediated neuronal death. Conversely, its overexpression enhanced cell death. TGM1 upregulation was mediated at the transcriptional level by an activator protein 1 (AP1) binding site that when mutated halted TGM1 promoter activation. These results indicate that TG1 acts downstream of A beta-toxicity, and that its stress-dependent increase makes it suitable for pharmacological intervention.