Role of Cell Cycle in Neurodegeneration

描述(申请人提供)：在以前的研究中，我们和其他人展示了一系列细胞周期相关蛋白在阿尔茨海默病(AD)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，并出现在疾病的最早前期(即轻度认知障碍)。此外，细胞周期蛋白代表了一个真实的细胞周期，而不是其他过程的附属物，证据表明AD患者神经元中存在真正的有丝分裂改变，导致DNA复制(即S期)。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，而且，MYC诱导的细胞周期重新进入导致tau磷酸化。基于这些体外实验结果，我们最近开发了一种双转基因小鼠模型，该模型可诱导前脑神经元特异性表达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)推动神经元进入细胞周期；2)导致tau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)导致胶质增生；6)导致主要的认知缺陷(Y迷宫和MWM)。由于上述病理和行为改变都是AD的同义词，因此该小鼠可能是一种非常有用的疾病发病机制模型。这项建议的目的是利用这个CaMKII-MYC动物模型(AIM 1)进一步阐明神经细胞周期再入的重要性，并通过分析一个三重转基因Tg2576/CaMKII-MYC小鼠(AIM 2)来研究富含A2条件下神经细胞周期再入的影响。在这些研究的结论中，我们不仅希望加深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。阿尔茨海默病是美国痴呆症的主要原因。最近的研究表明，脆弱神经元中不适当的细胞周期重新进入在神经元丢失、病理和认知障碍中发挥了作用，这些都是该病的特征。这一建议将有助于阐明细胞周期重入在阿尔茨海默病中的作用，方法是通过表征一种新的细胞周期重入转基因小鼠模型，并描述在富含淀粉样蛋白的环境中细胞周期重入的影响。

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.