Neurodegeneration by reactivation of cell cycle in neurons

描述（由申请人提供）：在以前的研究中，我们和其他人显示了阿尔茨海默病（AD）中特定脆弱神经元群体中许多细胞周期相关蛋白异常再表达的证据。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，这一点通过与AD中异常tau蛋白相比细胞周期蛋白的早期出现而得到强调。此外，细胞周期蛋白是真正的细胞周期的代表，而不是其他过程的附带现象，这是显而易见的，从最近的证据表明，在AD和其他神经退行性疾病，有一个真正的有丝分裂的改变，导致DNA复制。这些发现使我们提出了一个新的假设，即AD中的神经退行性病变与癌症一样，是一种细胞周期控制不当的疾病。为了描述成熟神经元中细胞周期再进入的重要性，我们最近开发了一种在前脑神经元中特异性诱导表达SV 40 T的双转基因小鼠模型（CaMKII-SV 40 T）。在我们对这些CaMKII-SV40T小鼠的初步分析中，我们发现SV40T表达驱动神经元重新进入细胞周期并导致tau蛋白过度磷酸化。本提案的目的是使用该CaMKII-SV40T小鼠进一步确定神经元细胞周期再进入的重要性。在这些研究的结论中，我们希望不仅能提高我们对神经元细胞周期重新进入的理解，特别是当它适用于AD时，而且还提出了新的治疗方法，可以被操纵来防止变性的开始或刺激神经退行性疾病中受损神经元的恢复。神经元细胞周期异常激活是阿尔茨海默病等神经退行性疾病的重要致病机制。然而，其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模型来研究体内成体神经元中的细胞周期再进入。因此，该项目的目标是使用新型转基因小鼠（CaMKII-SV 40 T）描述神经元细胞周期再进入的重要性，其中前脑神经元中的细胞周期再进入可以以诱导方式激活。

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.