Neurodegeneration by reactivation of cell cycle in neurons

描述(申请人提供)：在以前的研究中，我们和其他人证明了一些细胞周期相关蛋白在阿尔茨海默病(AD)的特定脆弱神经元群体中异常重新表达的证据。有丝分裂细胞周期相关机制可能在疾病发病机制中发挥重要作用，与异常tau相比，细胞周期蛋白在AD中出现得更早。此外，细胞周期蛋白代表了真实的细胞周期，而不是其他过程的附属物，最近的证据表明，在AD和其他神经退行性疾病中，存在真正的有丝分裂改变，导致DNA复制。这些发现导致我们提出了一个新的假设，即阿尔茨海默病中的神经退行性变，就像癌症一样，是一种细胞周期控制不当的疾病。为了阐明细胞周期重入成熟神经元的重要性，我们最近建立了一个双转基因小鼠模型，该模型可诱导前脑神经元特异性表达SV40T(CaMKII-SV40T)。在我们对这些CaMKII-SV40T小鼠的初步分析中，我们发现SV40T的表达驱动神经元重新进入细胞周期，并导致tau的过度磷酸化。这项建议的目的是利用这只CaMKII-SV40T小鼠进一步确定神经细胞周期重新进入的重要性。在这些研究的结论中，我们不仅希望加深我们对神经元细胞周期重入的后果的理解，特别是当它适用于AD时，还希望提出新的治疗方法，这些治疗方法可以被操纵来防止变性的开始或刺激神经变性条件下受损神经元的恢复。神经元细胞周期的异常激活现已成为阿尔茨海默病等神经退行性疾病中神经退行性变的关键致病机制。然而，它在疾病发病机制中的确切作用尚不清楚，主要是因为缺乏研究体内成年神经元细胞周期重新进入的研究模型。因此，该项目的目标是利用一种新型的转基因小鼠(CaMKII-SV40T)来描述神经元细胞周期重新进入的重要性，在这种小鼠中，前脑神经元的细胞周期重新进入可以被诱导的方式激活。

DESCRIPTION (provided by applicant): In previous studies, we and others showed evidence for the aberrant re-expression of a number of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease (AD). That a mitotic cell cycle-related mechanism may play an important role in disease pathogenesis is highlighted by the earlier occurrence of cell cycle proteins compared to abnormal tau in AD. Furthermore, that cell cycle proteins are representative of a true cell cycle, rather than being an epiphenomena of other processes, is evident from recent evidence showing that, in AD and other neurodegenerative diseases, there is a true mitotic alteration that leads to DNA replication. These findings led us to develop a novel hypothesis that neurodegeneration in AD, like cancer, is a disease of inappropriate cell cycle control. To delineate the importance of cell cycle re- entry in mature neurons, we have recently developed a bitransgenic mouse model that inducibly expresses SV40Tspecifically in forebrain neurons (CaMKII-SV40T). In our preliminary analysis of these CaMKII-SV40T mice, we found that SV40T expression drives neurons to re-enter the cell cycle and causes hyperphosphorylation of tau. The goal of this proposal is to further determine the importance of neuronal cell cycle re-entry using this CaMKII-SV40T mouse. At the conclusion of these studies, we hope to not only have advanced our understanding consequences of neuronal cell cycle re-entry, particularly as it applies to AD, but also suggest novel therapies that could be manipulated to either prevent initiation of degeneration or stimulate recovery of damaged neurons in neurodegenerative conditions. Aberrant cell cycle activation in neurons is now emerging as a key pathogenic mechanism of neurodegeneration in many neurodegenerative diseases such as Alzheimer disease. However, its exact role in disease pathogenesis is unclear primarily because of the absence of research models to study cell cycle re-entry in adult neurons in vivo. Therefore, the goal of the project is to delineate the importance of neuronal cell cycle re- entry using a novel transgenic mouse (CaMKII-SV40T) where cell cycle re-entry in forebrain neurons can be activated in an inducible manner.