Inhibiting the TOR Pathway to Combat Alzheimer's Disease

抑制 TOR 通路来对抗阿尔茨海默病

• 批准号: 8822003
• 负责人: Veronica Galvan
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822003
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Autophagocytosis; Blood Vessels; Brain; Carotid Artery Ulcerating Plaque; Cerebrovascular Circulation; Chronic; Clinic; Clinical Trials; Cognitive; Combined Modality Therapy; Complex; Data; Deposition; Deterioration; Disease; Disease Progression; Elderly; Endothelial Cells; Excision; FDA approved; Functional disorder; Future; Lead; Link; Magnetic Resonance Imaging; Measures; Mediating; Memory; Memory impairment; Metabolism; Mus; Nerve Degeneration; Onset of illness; Organ failure; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; Public Health; Research; Risk Factors; Safety; Sirolimus; Societies; South Texas; Testing; Tg2576; Therapeutic; Time; Transgenic Organisms; Translations; Vascular Dementia; Vascular Diseases; Veterans; age related; arm; cerebrovascular amyloid; cognitive function; combat; cost; data integrity; density; effective therapy; human NOS3 protein; improved; inhibitor/antagonist; insight; mouse model; neuron loss; neuropathology; prevent; protective effect; public health relevance; research study; restoration; secretase; tau-1

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.

描述（由申请人提供）： 阿尔茨海默病 (AD) 是主要的公共卫生问题之一，因为看似健康的人口老龄化可能导致美国社会每年损失超过 2000 亿美元，而大脑中淀粉样蛋白 -A 和磷酸化 tau 蛋白的积累是关键。复杂的神经退行性级联反应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，脑血管系统中聚集物的积累以及由此产生的血管功能障碍导致了 AD。迄今为止，雷帕霉素抑制细胞代谢的一个关键调节因子（雷帕霉素的靶点，TOR）和通过减少脑血流量（CBF）和损害耐受性而导致的退行性级联反应。是第一种经实验证明可以减缓小鼠衰老的药物，与这些观察结果一致，我们已经证明雷帕霉素可以阻止甚至挽救转基因中的 AD 样记忆缺陷。 hAPP(J20) 小鼠模拟了这种疾病 (Spilman et al 2009, Lin et al 2013)，这在其他 AD 模型中也有记录 (Caccamo et al 2010) 此外，我们发现雷帕霉素降低了大脑中的 A 水平并将其联系起来。我们实验室的最新研究（Lin et al 2013）表明，雷帕霉素的有益作用还涉及恢复血管密度和大脑。血流，这种效应依赖于脑血管系统中血管功能的主要调节剂内皮一氧化氮合酶 (eNOS) 的激活，因此雷帕霉素可以通过打破脑中 A 聚集体引发的恶性循环来增强记忆，而 A� 会增强这种恶性循环。我们将测试以下假设：雷帕霉素可以通过减少诱发的血管损伤和通过协同作用对小鼠的 AD 相关表型产生有益作用。通过 eNOS 恢复血管完整性，目的如下：（1）确定分泌酶抑制剂在药理上降低 A 是否能像雷帕霉素一样减轻血管损伤，以及雷帕霉素和 BSI 联合治疗是否对血管有协同作用(2) 评估雷帕霉素促进去除脑血管的机制；以及 (3) 探索雷帕霉素是否有效；通过激活 eNOS 恢复血管完整性和功能 该项目的相关性在于，它将进一步确定雷帕霉素或其他潜在 TOR 抑制剂在 AD 治疗中的治疗潜力，并且还将增加我们对雷帕霉素在 AD 中作用机制的理解。此外，我们的项目具有外在的优点，它将提供联合疗法的潜力，这可能是有效治疗 AD 的关键，TOR 抑制剂已获得 FDA 批准并用于临床，并且最近进行了一项试点研究。经过我们在南德克萨斯退伍军人管理局的合作者表明，雷帕霉素作为单一治疗方法对健康老年人来说是安全的，因此我们的研究对患有 AD 的退伍军人具有直接的转化潜力，因为临床试验在不久的将来是可行的，因为雷帕霉素可以预防脑血管功能障碍。衰老是衰老的普遍特征，我们的研究结果有可能适用于与年龄相关的神经病理学，例如血管性痴呆和帕金森病。