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。我们和其他人已经证明了细胞周期相关蛋白在AD的脆弱神经元中的表达。这代表了真正的有丝分裂事件的证据被DNA复制在这些细胞中发生的观察所证明。与其他病理学相比，细胞周期事件的发生更早，这表明有丝分裂细胞周期相关机制可能在AD中发挥作用。细胞周期事件在疾病中的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系中，如Tg 2576，细胞周期蛋白和染色体复制增加，并且这种变化早于淀粉样蛋白-2沉积。其次，我们最近开发了一种专门的转基因模型（CaMKII-MYC）的神经元特异性诱导癌基因驱动的细胞周期，特异性表达myc在前脑神经元。对这些动物的分析表明，MYC表达导致细胞周期重新进入，导致tau磷酸化、淀粉样蛋白-b的神经元内积累、神经变性和认知缺陷。这些转基因株系的观察结果表明，异常细胞周期控制是AD发病机制中的早期和可能的关键因素。我们建议通过在Tg 2576和CaMKII-MYC转基因模型中抑制细胞周期重新进入来测试这一概念。使用roscovitine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学（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。在这些研究的这一结论中，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.