Challenges in neuronal apoptosis
Challenges in neuronal apoptosis
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DOI：
10.2174/156720506778249434
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发表时间：
2006-09-01
影响因子：
2.1
通讯作者：
Jellinger, Kurt A.
中科院分区：
文献类型：
--
作者：
Jellinger, Kurt A.
神经元死亡的原因和方式多种多样，其中凋亡是一种特殊的形式，在两种主要的信号通路中进行，TNF受体介导的（外源性）和基于神经元的（内源性）细胞死亡通路，它们之间存在几种串扰途径。细胞凋亡的分子关键球员，通过与不同的死亡效应结构域的相互作用的Csp级联的重要性和作用的效应Csp-3驱动的细胞死亡程序的执行进行了审查。最近的数据表明，半胱天冬酶融合淀粉样蛋白和tau阿尔茨海默病病理学：β淀粉样蛋白肽激活半胱天冬酶，其转而切割tau并通过tau的磷酸化引发阿尔茨海默病和其他tau病变中的缠结病理学。几种介质显示出凋亡的双功能调节，具有促凋亡和抗凋亡活性。后者由于抑制Csp活化或其他保护机制而改变细胞死亡途径，并且可以延迟它，或者通过流产凋亡（“流产”）导致神经细胞的存活延长。虽然细胞凋亡在神经退行性变中的作用在组织培养和转基因动物模型中得到了很好的证明，但在人类死后AD脑中，其发生和作用仍有争议。考虑到阿尔茨海默病和相关疾病中完成细胞凋亡和慢性进行性过程或神经变性所需的短时间，尽管具有DNA片段化的细胞（主要是神经胶质细胞）的发生率显著增加，但检测显示细胞凋亡的形态学迹象和活化的关键执行酶Csp-3的表达的罕见神经元是现实的。老年人大脑中“促凋亡”环境的标记物表明神经元对代谢和其它有害因素的敏感性增加。死后分析可以弥合我们的一些但不是所有知识差距，但结果仍然存在争议，我们需要更好地理解或驱动神经元存活和死亡之间阴阳的分子基础和途径。
There are myriads of reasons and ways for a neuron to die, among which apoptosis is a specific form that is processed in two major signaling pathways, the TNF-receptor-mediated (extrinsic) and the mitochondria-based (intrinsic) cell death pathway with several avenues of crosstalk between them. The molecular key players of apoptosis, the importance of the Csp cascade via interaction with different death effector domains and the role of the effector Csp-3 driving the execution of the cell death program are reviewed. Recent data suggest that caspases converge amyloid and tau Alzheimer pathologies: beta amyloid peptide activates caspases which on turn cleave tau and via phosphorylation of tau initiate tangle pathology in both Alzheimer disease and other tauopathies. Several mediators show a bifunctional regulation of apoptosis, with both pro- and anti-apoptotic activities. The latter modify the cell death pathway due to inhibition of Csp activation or other protective mechanisms and may delay it or, via abortive apoptosis ("abortosis") lead to prolonged survival of nerve cells. While the role of apoptosis in neurodegeneration is well documented in tissue culture and transgenic animal models, in human postmortem AD brain its occurrence and role are discussed controversially. Given the short duration required for the completion of apoptosis and the chronic progressive course or neurodegeneration in Alzheimer disease and related disorders, the detection of rare neurons displaying morphological signs of apoptosis and expression of the activated key-executing enzyme Csp-3 is realistic, although there is significantly increased incidence of cells with DNA fragmentaion, mainly glia, and markers for a "proapoptotic" environment in the aged human brain indicate increased susceptibility of neurons to metabolic and other noxious factors. Postmortem analysis can bridge some but not all of our knowledge gaps, but the results are still controversial, and we need a better understanding or the molecular basis and pathways that drive the yin-yang between neuronal survival and death.