Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases.
Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases.
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DOI：
10.1186/alzrt5
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发表时间：
2009-10-12
期刊：
影响因子：
--
通讯作者：
Miller VM
中科院分区：
文献类型：
--
作者：
Golde TE;Miller VM
阿尔茨海默病（AD）和许多其他神经退行性中枢神经系统（CNS）蛋白质病的特征在于错误折叠的蛋白质聚集体的积累。简单地说，这些聚集体可分为较小的可溶性低聚物和较大的不太可溶或不可溶的纤维状形式。也许在神经退行性疾病领域正在进行的主要争论是较小的寡聚体或较大的纤维状聚集体是否是主要的神经毒素。在此，我们提出了一个整合的假设，提供了新的见解，如何各种错误折叠的蛋白质聚集体可以导致神经退行性变。我们介绍的概念，广泛的高度稳定的错误折叠的蛋白质聚集体在AD和其他神经退行性蛋白质病被认为是非自我和慢性激活先天免疫系统。这种促炎状态导致CNS细胞的生理衰老。一旦CNS细胞经历生理衰老，它们就会分泌多种促炎分子。因此，最初由炎症刺激触发的细胞衰老成为进一步炎症和衰老的自我强化刺激。最终，衰老的CNS细胞功能受损并最终死亡，这种神经变性导致脑器官衰竭。这种综合性假说，我们将其称为AD和其他神经退行性疾病的蛋白质病诱导的衰老细胞假说，将CNS蛋白质病与炎症、生理衰老、细胞功能障碍和最终神经退行性疾病联系起来。未来的研究特征的衰老表型的中枢神经系统细胞在AD和其他神经退行性疾病将测试这一假设的有效性。中枢神经系统衰老的影响作为一个促成因素的神经退行性级联反应及其治疗的影响进行了讨论。
Alzheimer's disease (AD) and a host of other neurodegenerative central nervous system (CNS) proteinopathies are characterized by the accumulation of misfolded protein aggregates. Simplistically, these aggregates can be divided into smaller, soluble, oligomeric and larger, less-soluble or insoluble, fibrillar forms. Perhaps the major ongoing debate in the neurodegenerative disease field is whether the smaller oligomeric or larger fibrillar aggregates are the primary neurotoxin. Herein, we propose an integrative hypothesis that provides new insights into how a variety of misfolded protein aggregates can result in neurodegeneration. We introduce the concept that a wide range of highly stable misfolded protein aggregates in AD and other neurodegenerative proteinopathies are recognized as non-self and chronically activate the innate immune system. This pro-inflammatory state leads to physiological senescence of CNS cells. Once CNS cells undergo physiological senescence, they secrete a variety of pro-inflammatory molecules. Thus, the senescence of cells, which was initially triggered by inflammatory stimuli, becomes a self-reinforcing stimulus for further inflammation and senescence. Ultimately, senescent CNS cells become functionally impaired and eventually die, and this neurodegeneration leads to brain organ failure. This integrative hypothesis, which we will refer to as the proteinopathy-induced senescent cell hypothesis of AD and other neurodegenerative diseases, links CNS proteinopathies to inflammation, physiological senescence, cellular dysfunction, and ultimately neurodegeneration. Future studies characterizing the senescent phenotype of CNS cells in AD and other neurodegenerative diseases will test the validity of this hypothesis. The implications of CNS senescence as a contributing factor to the neurodegenerative cascade and its implications for therapy are discussed.
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影响因子：
7.7
作者：
Augert, Arnaud;Payre, Christine;Bernard, David
通讯作者：
Bernard, David
影响因子：
82.9
作者：
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通讯作者：
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DOI：
10.1158/1541-7786.mcr-08-0062
发表时间：
2008-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
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通讯作者：
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影响因子：
5.5
作者：
Bitan, G;Fradinger, EA;Teplow, DB
通讯作者：
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影响因子：
5.3
作者：
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