Cell Cycle Inhibitors in Alzheimer Disease

描述（由申请人提供）：不适当的细胞周期控制正在成为导致阿尔茨海默病（AD）发病机制的重要组成部分。我们和其他人已经在阿尔茨海默病的易感神经元中发现了细胞周期相关蛋白的表达。有证据表明，这是一个真正的有丝分裂事件，通过观察DNA复制发生在这些细胞中，证明了这一点。与其他病理相比，细胞周期事件的早期发生表明有丝分裂细胞周期相关机制可能在AD中起作用。其他支持细胞周期事件在疾病中的重要作用的证据来自转基因动物模型。首先，在具有高淀粉样蛋白负荷的转基因系中，如Tg2576，细胞周期蛋白和染色体复制增加，这些变化早于淀粉样蛋白-2沉积。其次，我们最近开发了一种神经元特异性诱导癌基因驱动细胞周期的专用转基因模型（CaMKII-MYC），该模型在前脑神经元中特异性表达myc。对这些动物的分析表明，MYC表达导致细胞周期再进入，导致tau磷酸化、淀粉样蛋白b在神经元内积聚、神经变性和认知缺陷。这些转基因细胞系的观察结果指出，异常细胞周期控制是阿尔茨海默病发病的早期和关键因素。我们建议通过在Tg2576和CaMKII-MYC转基因模型中抑制细胞周期再进入来验证这一概念。使用罗斯维汀阻断细胞周期再进入，我们将评估细胞周期再进入在这些小鼠中观察到的病理（包括神经元变性、tau磷酸化、淀粉样蛋白b）和行为缺陷（如莫里斯水迷宫）中的作用。在这些研究的结论中，预计我们不仅将认识到细胞周期介导的事件在疾病发病机制的其他方面的作用，而且还将认识到使用细胞周期抑制方法作为AD治疗方案的潜在效用。

DESCRIPTION (provided by applicant): Inappropriate cell cycle control is emerging as an important component in the pathogenesis leading to Alzheimer disease (AD). We and others have shown expression of cell cycle-related proteins in the vulnerable neurons in AD. Evidence that this represents a bona fide mitotic event is proved by the observation that DNA replication is occurring in these cells. The earlier occurrence of cell cycle events compared to other pathologies suggests that a mitotic cell cycle-related mechanism may play a role in AD. Additional supportive evidence for an important role for cell cycle events in disease derives from transgenic animal models. First, in transgenic lines with a high amyloid burden, such as Tg2576, there are increases in cell cycle proteins and chromosome duplication and such changes predate frank amyloid-2 deposition. Second, we recently developed a dedicated transgenic model (CaMKII-MYC) of neuron-specific inducible oncogene driven cell cycle that specifically expresses myc in forebrain neurons. Analysis of such animals shows that MYC expression results in cell cycle re-entry leading to tau phosphorylation, intraneuronal accumulation of amyloid-b, neurodegeneration, and cognitive deficits. The observations from these transgenic lines pinpoint abberant cell cycle control as an early and perhaps pivotal factor in the pathogenesis of AD. We propose to test this notion by inhibiting cell cycle re-entry in both Tg2576 and CaMKII-MYC transgenic models. Using roscovitine to block cell cycle re-entry, we will assess the role of cell cycle re-entry in the pathology (including neuronal degeneration, tau phosphorylation, amyloid-b) and behavioral deficits (such as Morris Water Maze) observed in these mice. At this conclusion of these studies, it is anticipated that we will not only realize the role of cell cycle-mediated events in relation to other aspects of disease pathogenesis but also the potential utility of using cell cycle inhibitory approaches as a therapeutic regimen in AD.