Mechanisms of neuronal death in Alzheimer's disease
Mechanisms of neuronal death in Alzheimer's disease
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DOI：
10.1111/j.1750-3639.1996.tb00878.x
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发表时间：
1996-10-01
期刊：
影响因子：
6.4
通讯作者：
Su, JH
中科院分区：
文献类型：
--
作者：
Cotman, CW;Su, JH
细胞培养的最新数据表明，脑神经元特别容易因细胞凋亡而退化。此外，激活程序的诱导物（例如β-淀粉样蛋白、氧化性损伤、低能量代谢）对应于阿尔茨海默病（AD）脑中存在的状况。这表明细胞凋亡可能是导致这种疾病中神经元丢失的机制之一。事实上，AD脑的脆弱区域中的一些神经元显示DNA损伤、核凋亡小体、染色质浓缩以及细胞培养物和动物模型中诱导细胞凋亡的选择基因特征的证据。这表明AD脑中存在细胞凋亡，这一假设也与早老素基因的调节功能之一的不断发展的研究一致。另一方面，在早期和轻度病例中，脆弱区域的大多数神经元都存在DNA损伤。在大多数组织中，处于完全激活的凋亡中的细胞退化并在数小时至数天内被移除，因此似乎所有DNA损伤都不太可能意味着终末凋亡。广泛的DNA损伤的存在表明损伤的加速、错误的修复过程、保护机制的丧失或凋亡程序的激活和停滞。DNA损伤不太可能是死后延迟或濒死状态的人为因素。神经元的保护机制可能存在，因为这些细胞是不可分裂的和必需的。在这种情况下，有趣的是，Bcl-2在大多数DNA损伤的神经元中上调。此外，至少一种DNA修复酶也被上调。因此，神经元似乎处于退化和修复之间的斗争中。随着研究的深入，减少导致神经元损伤的刺激并发现关键干预点以帮助神经元修复过程至关重要。
Recent data in cell culture has shown that brain neurons are particularly vulnerable to degeneration by apoptosis. Further the inducers that activate the program (e.g. beta-amyloid, oxidatative damage, low energy metabolism) correspond to conditions present in the Alzheimer's disease (AD) brain. This suggests the possibility that apoptosis may be one of the mechanisms contributing to neuronal loss in this disease. Indeed, some neurons in vulnerable regions of the AD brain show evidence of DNA damage, nuclear apoptotic bodies, chromatin condensation, and the induction of select genes characteristic of apoptosis in cell culture and animal models. This suggests the existence of apoptosis in the AD brain, a hypothesis also consistent with evolving research in one of the regulatory functions of the presenilin genes. On the other hand, DNA damage is present in the majority of neurons in vulnerable regions in early and mild cases. In most tissues, cells in fully activated apoptosis degenerate and are removed within hours to days and thus it seems all DNA damage is unlikely to signify terminal apoptosis. The presence of extensive DNA damage suggests an acceleration of damage, faulty repair process, loss of protective mechanisms, or an activation and arrest of aspects of the apoptotic program. DNA damage is unlikely to be an artifact of postmortem delay or agonal state. The existence of protective mechanisms for neurons may exist as these cells are nondividing and essential. In this context it is interesting that Bcl-2 is upregulated in most neurons with DNA damage. Further, at least one DNA repair enzyme is also upregulated. Thus it appears as if neurons are in a struggle between degeneration and repair. As research advances it is critical to reduce the stimuli that cause the neuronal damage and discover the key intervention points to assist neurons in the repair processes.