Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
Alzheimers Res Ther. 2009 Oct 12;1(2):5. doi: 10.1186/alzrt5.
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.
阿尔茨海默病（AD）和许多其他神经退行性中枢神经系统（CNS）蛋白病的特征是错误折叠的蛋白质聚集体的积累。简单地说，这些聚集体可以分为较小的、可溶性的、寡聚体和较大的、较少溶解或不溶解的、纤维状形式。也许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，我们提出了一个综合假说，为理解各种错误折叠的蛋白质聚集体如何导致神经退行性变提供了新的见解。
我们提出了一个概念，即在 AD 和其他神经退行性蛋白病中，广泛存在的高度稳定的错误折叠蛋白聚集体被认为是非自身的，并慢性激活固有免疫系统。这种促炎状态导致中枢神经系统细胞的生理衰老。一旦中枢神经系统细胞经历生理衰老，它们就会分泌各种促炎分子。因此，最初由炎症刺激引发的细胞衰老，成为进一步炎症和衰老的自我强化刺激。最终，衰老的中枢神经系统细胞功能受损并最终死亡，这种神经退行性变导致脑器官衰竭。
这个综合假说，我们将其称为 AD 和其他神经退行性疾病的蛋白病诱导衰老细胞假说，将中枢神经系统蛋白病与炎症、生理衰老、细胞功能障碍联系起来，并最终导致神经退行性变。未来对 AD 和其他神经退行性疾病中中枢神经系统细胞衰老表型的研究将检验这一假说的有效性。讨论了中枢神经系统衰老作为神经退行性级联的一个促成因素及其对治疗的影响。
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