Cell Cycle Activation and Aneuploid Neurons in Alzheimer's Disease
Cell Cycle Activation and Aneuploid Neurons in Alzheimer's Disease
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DOI：
10.1007/s12035-012-8262-0
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发表时间：
2012-08-01
影响因子：
5.1
通讯作者：
Arendt, Thomas
中科院分区：
文献类型：
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作者：
Arendt, Thomas
阿尔茨海默病(AD)是一种慢性神经退行性疾病，其特征是突触变性，伴随着淀粉样肽和微管相关蛋白tau的纤维聚集。在AD期间，整个大脑的神经纤维变性的进展遵循一个预测性的模式，这为疾病的神经病理分期提供了基础。这种针对神经纤维变性的选择性神经元脆弱性模式与神经元可塑性的区域程度相匹配，并反过来概括了将神经退行性细胞死亡与神经可塑性和脑发育联系起来的个体发育和系统发育脑发育。在这里，我们总结了最近的证据表明，神经元分化控制的丧失是AD的一个关键致病事件，与细胞周期的重新激活和DNA的部分或全部复制有关，从而产生DNA含量高于二倍体水平的神经元。具有非整倍体染色体的神经元也以较低的频率出现在正常大脑中，在那里它们似乎具有很好的耐受性。然而，在AD中，非整倍体神经元的数量高度增加，具有这种染色体异常的神经元会发生相当选择性的细胞死亡。这一发现将非整倍体添加到神经退行性变和肿瘤发生之间共享的关键分子事件的列表中。它定义了神经元易损性的分子特征，并将我们的注意力转向神经元分化控制的失败，作为AD的关键致病事件和潜在的治疗靶点。
Alzheimer's disease (AD) is a chronic neurodegenerative disorder, characterized by synaptic degeneration associated with fibrillar aggregates of the amyloid- peptide and the microtubule-associated protein tau. The progression of neurofibrillary degeneration throughout the brain during AD follows a predictive pattern which provides the basis for the neuropathological staging of the disease. This pattern of selective neuronal vulnerability against neurofibrillary degeneration matches the regional degree of neuronal plasticity and inversely recapitulates ontogenetic and phylogenetic brain development which links neurodegenerative cell death to neuroplasticity and brain development. Here, we summarize recent evidence for a loss of neuronal differentiation control as a critical pathogenetic event in AD, associated with a reactivation of the cell cycle and a partial or full replication of DNA giving rise to neurons with a content of DNA above the diploid level. Neurons with an aneuploid set of chromosomes are also present at a low frequency in the normal brain where they appear to be well tolerated. In AD, however, where the number of aneuploid neurons is highly increased, a rather selective cell death of neurons with this chromosomal aberrancy occurs. This finding add aneuploidy to the list of critical molecular events that are shared between neurodegeneration and oncogenesis. It defines a molecular signature for neuronal vulnerability and directs our attention to a failure of neuronal differentiation control as a critical pathogenetic event and potential therapeutic target in AD.