Inhibiting the TOR Pathway to Combat Alzheimer's Disease

描述(由申请人提供)： 随着看似健康的人群老龄化，阿尔茨海默病(AD)是主要的公共卫生问题之一。广告每年可能要花费美国社会2000多亿美元。淀粉样蛋白-�A�和磷酸化tau在大脑中的积累被认为是复杂的神经退行性变级联反应的关键因素，最终导致广泛的脑器官衰竭，从而导致症状性AD。越来越多的数据表明，聚集体在脑血管系统中的积累和由此导致的血管功能障碍通过减少脑血流量和损害A�学习而导致退行性级联反应。到目前为止，高龄是AD的最大风险因素。雷帕霉素抑制细胞代谢的关键调节剂(雷帕霉素的靶标，TOR)，是第一种被实验证明可以延缓小鼠衰老的药物。与这些观察一致，我们已经表明雷帕霉素可以阻止甚至挽救建模疾病的转基因HAPP(J20)小鼠的AD样记忆缺陷(Spilman等人2009，Lin等人2013年)，这也在其他AD模型中得到了证明(Caccamo等人2010年)。此外，我们发现雷帕霉素降低了大脑中的A水平，并将这种降低与自噬的激活联系在一起。我们实验室的最新研究(Lin等2013)表明，雷帕霉素的有益作用还包括恢复血管密度和脑血流量，这种作用依赖于脑血管系统中血管功能的主要调节因子-内皮型一氧化氮合酶(ENOS)的激活。因此，雷帕霉素可能通过打破由脑内聚集体引发的恶性循环来增强记忆，这种恶性循环因A�导致的血管恶化而得到加强。我们将检验这一假设，即雷帕霉素可以通过减少A�引起的血管损伤以及通过eNOS恢复血管完整性来协同作用于AD相关表型，其目的如下：(1)确定用雷帕霉素协同治疗A�是否能以与雷帕霉素相同的程度减少血管损伤，以及与�联合治疗是否对血管功能具有协同作用；(2)评估雷帕霉素可促进A�从脑血管系统移除的机制；以及(3)探讨雷帕霉素是否通过激活eNOS来恢复血管完整性和功能。该项目的意义在于，它将进一步确立雷帕霉素或其他潜在的TOR抑制剂在治疗AD方面的治疗潜力，并将增加我们对雷帕霉素在AD脑中作用机制的理解。此外，我们的项目具有外在的优点，它将提供对联合疗法潜力的洞察，这可能是有效治疗AD的关键。Tor抑制剂是FDA批准并用于临床的，我们在南得克萨斯州弗吉尼亚州的合作者最近进行的一项试点研究表明，雷帕霉素作为健康老年人的单一治疗方法是安全的，因此我们的研究对患有AD的退伍军人具有直接的翻译潜力，因为临床试验将在不久的将来可行。由于雷帕霉素可以预防脑血管功能障碍，这是衰老的一个普遍特征，我们的发现有可能适用于其他与年龄相关的神经病理，如血管性痴呆和各种帕金森氏病。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the major public health concerns as seemingly healthy populations age. AD may cost American society more than $200 billion dollars per year. Accumulation of amyloid-�A�and phosphorylated tau in the brain is proposed to be key factors in a complex neurodegenerative cascade that eventually leads to widespread brain organ failure resulting in symptomatic AD. Increasing data suggest that accumulation of Aaggregates in the cerebrovasculature and the resulting vessel dysfunction contribute to degenerative cascades by diminishing cerebral blood flow (CBF) and by impairing A�learance. Advanced age is, by far, the greatest risk factor for AD. Rapamycin inhibits a key regulator of cellular metabolism (the target-of-rapamycin, TOR) and is the first drug that has been experimentally proven to slow aging in mice. Consistent with these observations, we have shown that rapamycin halts and even rescues AD- like memory deficits in transgenic hAPP(J20) mice modeling the disease (Spilman et al 2009, Lin et al 2013), and this was also documented in other AD models (Caccamo et al 2010). Further, we found that rapamycin decreased Alevels in the brain and linked this decrease to the activation of autophagy. More recent studies from our lab (Lin et al 2013) indicate that beneficial effects of rapamycin also involve the restoration vascular density and cerebral blood flow, an effect dependent on the activation of endothelial nitric oxide synthase (eNOS), a major regulator of vascular function, in brain vasculature. Thus rapamycin may enhance memory by breaking a vicious cycle initiated by Aaggregates in brain that is reinforced by A�nduced vascular deterioration. We will test the hypothesis that rapamycin can synergistically have beneficial actions on AD relevant phenotypes in mice by decreasing A�nduced vascular damage and by restoring vascular integrity through eNOS with the following aims: (1) Determine whether pharmacologically lowering of A�ith a �ecretase inhibitor can reduce vascular damage to the same extent as rapamycin and whether combination therapy with rapamycin and a BSI has a synergistic effect on vascular function; (2) Evaluate mechanisms whereby rapamycin could facilitate the removal of A�y the cerebrovasculature; and (3) Explore whether rapamycin restores vascular integrity and function through the activation of eNOS. The relevance of this project is that it will further establish the therapeutic potential for rapamycin or potentially other TOR inhibitors in the treatment of AD, and will also increase our understanding of mechanisms of rapamycin action in AD brain. Furthermore, our project has extrinsic merit in the insight it will provide on the potential of combination therapies, which may be key to effective treatment of AD. TOR inhibitors are FDA- approved and used in the clinic, and a recent pilot study by our collaborators at the South Texas VA suggets safety of rapamycin as a single treatment in healthy elderly, thus our research has immediate translational potential for Veterans suffering from AD since clinical trials would be feasible in the near future. Because rapamycin prevents brain vascular dysfunction, a universal feature of aging, our findings have the potential to be applicable to othe age-related neuropathologies such as vascular dementia and forms of Parkinson's disease.