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)的发病机制的重要组成部分。我们和其他人已经在AD的脆弱神经元中发现了细胞周期相关蛋白的表达。观察到这些细胞中正在发生DNA复制，这证明了这是一种真正的有丝分裂事件。与其他病理相比，细胞周期事件的发生较早，提示有丝分裂细胞周期相关机制可能在AD中起作用。细胞周期事件在疾病中发挥重要作用的其他支持性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品系中，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。第二，我们最近建立了一个专门的转基因模型(CaMKII-MYC)，它是神经元特异性的可诱导癌基因驱动的细胞周期，在前脑神经元中特异性地表达myc。对这类动物的分析表明，MYC的表达导致细胞周期重新进入，导致tau磷酸化，淀粉样蛋白-b在神经元内积累，神经退化和认知缺陷。来自这些转基因株系的观察准确地指出，疏松的细胞周期控制是阿尔茨海默病发病的早期因素，也可能是关键因素。我们建议在Tg2576和CaMKII-MYC转基因模型中通过抑制细胞周期重新进入来测试这一观点。使用罗可维汀阻断细胞周期重入，我们将评估细胞周期重入在这些小鼠观察到的病理(包括神经元变性、tau磷酸化、淀粉样蛋白-b)和行为缺陷(如Morris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中的其他方面的作用，而且将细胞周期抑制方法用作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.