Role of Cell Cycle in Neurodegeneration

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一系列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起重要作用，这通过与AD中的异常tau相比细胞周期蛋白的更早出现以及它们在疾病的最早前驱期（即，轻度认知障碍）。此外，细胞周期蛋白是真实细胞周期的代表，而不是其他过程的附带现象，这从显示存在导致DNA复制的真实有丝分裂改变（即，S期）。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。基于这些体外研究结果，我们最近开发了一种双转基因小鼠模型，可诱导表达MYC特异性前脑神经元（CaMKII-MYC）。在我们对这些CaMKII-MYC动物的初步分析中，我们发现该动物模型中的MYC表达：1）驱动神经元进入细胞周期; 2）引起tau的过度磷酸化; 3）导致神经元内AB的积累; 4）导致“神经变性”（TUNEL）表型; 5）导致神经胶质增生;和6）引起主要认知缺陷（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。本提案的目的是使用该CaMKII-MYC动物模型进一步描述神经元细胞周期再进入的重要性（目的1），并通过分析三重转基因Tg 2576/CaMKII-MYC小鼠来检查在富含A2的条件下神经元细胞周期再进入的影响（目的2）。在这些研究的结论，我们希望不仅有先进的控制神经元细胞周期的基本机制，我们的理解，特别是因为它适用于AD，但也提出了新的疗法，可以操纵，以防止开始变性或刺激神经退行性疾病中受损神经元的恢复。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再进入在神经元丢失、病理学和认知障碍中起作用，这些都是疾病的特征。这一建议将有助于澄清细胞周期重入阿尔茨海默病的作用，通过表征一种新的转基因小鼠模型的细胞周期重入和描绘的影响，细胞周期重入在富含淀粉样蛋白的环境。

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.