Role of Cell Cycle in Neurodegeneration

描述（由申请人提供）：在之前的研究中，我们和其他人发现了阿尔茨海默病（AD）特定易感神经元群体中一系列细胞周期相关蛋白异常重新表达的证据。有丝分裂细胞周期相关的机制可能在疾病发病机制中发挥重要作用，这一点通过在AD中较早出现细胞周期蛋白而不是异常的tau蛋白以及它们在疾病的最早前体期（即轻度认知障碍）出现而得到强调。此外，细胞周期蛋白代表了真正的细胞周期，而不是其他过程的副现象，证据表明，阿尔茨海默病神经元中存在导致DNA复制的真正有丝分裂改变（即S期）。这些发现使我们提出了一种新的假设，即阿尔茨海默病的神经退行性变，就像癌症一样，是一种细胞周期控制不当的疾病。为了支持这一观点，我们发现一种强大的细胞周期诱导剂MYC的表达驱动原代神经元重新进入细胞周期，此外，MYC诱导的细胞周期重新进入导致tau磷酸化。基于这些体外研究结果，我们最近开发了一种双基因小鼠模型，可以诱导在前脑神经元中特异性表达MYC （CaMKII-MYC）。在我们对这些CaMKII-MYC动物的初步分析中，我们发现MYC在该动物模型中的表达：1)驱动神经元进入细胞周期；2)引起tau蛋白的过度磷酸化；3)导致神经元内AB的积累；4)导致“神经退行性”（TUNEL）表型；5)导致胶质瘤；6)导致严重的认知缺陷（Y迷宫和MWM）。由于上述病理和行为变化都与AD同义，因此该小鼠可能是一种非常有用的疾病发病机制模型。本提案的目标是利用CaMKII-MYC动物模型（目的1）进一步描述神经细胞周期再进入的重要性，并通过分析三重转基因Tg2576/CaMKII-MYC小鼠（目的2）来检查在富含a2条件下神经细胞周期再进入的影响。在这些研究的结论中，我们希望不仅能提高我们对控制神经元细胞周期的基本机制的理解，特别是当它适用于阿尔茨海默病时，而且还能提出新的治疗方法，可以用来防止神经退行性疾病中退化的开始或刺激受损神经元的恢复。阿尔茨海默病是美国痴呆症的主要原因。最近的研究表明，在易感神经元中，不适当的细胞周期再进入在神经元丢失、病理和认知障碍中起作用，这些都是该疾病的特征。这一建议将有助于阐明细胞周期再进入在阿尔茨海默病中的作用，通过描述一种新的细胞周期再进入的转基因小鼠模型，并描述在富含淀粉样蛋白的环境中细胞周期再进入的影响。

DESCRIPTION (provided by applicant): In previous studies, we and others showed evidence for the aberrant re-expression of a series 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 and by their appearance at the very earliest prodrominal phase of disease (i.e., mild cognitive impairment). Furthermore, that cell cycle proteins are representative of a true cell cycle, rather than being an epiphenomena of other processes, is evident from evidence showing that there is a true mitotic alteration that leads to DNA replication (i.e., S phase) in neurons in AD. These findings led us to develop a novel hypothesis that neurodegeneration in AD, like cancer, is a disease of inappropriate cell cycle control. In support of this notion, we found that the expression a powerful cell cycle inducer, MYC, drives primary neurons to re-enter the cell cycle and, moreover, that MYC-induced cell cycle re-entry leads to tau phosphorylation. Based on these in vitro findings, we have recently developed a bitransgenic mouse model that inducibly expresses MYC specifically in forebrain neurons (CaMKII-MYC). In our preliminary analysis of these CaMKII-MYC animals, we found that MYC expression in this animal model: 1) drives neurons to enter the cell cycle; 2) causes hyperphosphorylation of tau; 3) leads to accumulation of intraneuronal AB; 4) results in a "neurodegenerative" (TUNEL) Phenotype; 5) leads to gliosis; and 6) causes major cognitive deficits (Y- maze and MWM). Since the aforementioned pathological and behavioral changes are all synonymous with AD, this mouse may be a very useful model of disease pathogenesis. The goal of this proposal is to further delineate the importance of neuronal cell cycle re-entry using this CaMKII-MYC animal model (Aim 1) and examine the effects of neuronal cell cycle re-entry under A2-rich conditions by analysis of a triple transgenic Tg2576/CaMKII-MYC mice (Aim 2). At the conclusion of these studies, we hope to not only have advanced our understanding of fundamental mechanisms that control neuronal cell cycle, 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. Alzheimer disease is the leading cause of dementia in the United States. Recent studies have implicated inappropriate cell cycle re-entry in vulnerable neurons as playing a role in the neuronal loss, pathology, and cognitive impairment that are characteristic of the disease. This proposal will help to clarify the role of cell cycle re-entry in Alzheimer disease by characterizing a novel transgenic mouse model of cell cycle re-entry and delineating the effects of cell cycle re-entry in an amyloid-rich environment.