Mitochondrial Complex I as a Target for Neuroprotection in AD

阿尔茨海默病 (AD) 没有有效的治疗方法，最近的临床试验侧重于预防淀粉样变性 类β (Ab) 生产一直失败。迫切需要替代方法。我们恶魔- 指出用小分子 CP2 部分抑制线粒体复合物 I 可以诱导神经保护作用 多种家族性 AD 小鼠模型。虽然复合物 I 活性的抑制与延长长链相关 gevity，我们是第一个证明这种方法对 AD 有益的人。 CP2穿透血脑 屏障，并在线粒体中积累，与黄素单核苷酸竞争结合 复合物 I 的氧化还原中心。复合物 I 活性的部分抑制诱导细胞对氧化的有益适应 应激和细胞能量的增强，这与发育的显着延迟有关 当独立的 AD 小鼠组在治疗前或治疗前接受治疗时，认知和行为表型的变化 疾病的症状阶段。然而，除了治疗的好处外，包括减少 可溶性和不溶性 Ab 和 pTau，抑制糖原合酶激酶 3b 活性，恢复轴突交通 脑源性神经营养因子和突触蛋白的 fick 和水平，CP2 诱导的 AMP 激活 激活蛋白激酶（AMPK）。考虑到与 AMPK 相关的有害影响 激活人类，利用线粒体复合物 I 实现有效且安全的治疗反应 AD背景下的抑制剂，必须了解分子机制以避免反式失败 将我们的发现应用到临床环境中。具体实验目标是：1）检验中心假设 CP2 诱导的神经保护不需要激活 AMPK； 2）确定mo的层次结构 AMPK 激活以外的分子机制参与神经保护； 3）确认这些机制 在表达人 Aβ 和 Tau 蛋白 (3xTgAD) 的 AD 小鼠模型中，以及在小鼠中敲除 ApoE4 类似于散发性 AD； 4) 建立基于血液的生物标志物，用于转化研究的目标参与； 5) 确定该方法在人类神经元细胞中的转化潜力；和 6) 进行 Pharma- 使用来自不同健康人群的淋巴母细胞系进行宏基因组学研究，以建立安全标准 杜松子酒和对治疗的个体化反应。 拟议的研究将对 CP2 神经促进剂所必需的分子机制进行严格的评估。 保护，并将利用靶向遗传研究这种方法治疗 AD 的转化潜力和安全性 多个小鼠和人类模型系统中的扰动和先进技术。结果将合理 开发联合疗法以减轻潜在的有害副作用，并开发生物标志物来监测 目标参与度和安全性。由于大多数实验将与metfor同时进行 分钟，唯一被 FDA 批准用于治疗糖尿病的复合物 I 抑制剂，其结果也将提供关键的 校准生物学证据以确定基本原理和临床前标准，以支持进一步的临床开发 用于 AD 治疗的特定 MCI 抑制剂。 ！ ！ ！

Alzheimer's Disease (AD) has no effective treatments, and recent clinical trials focused on prevention of amy- loid beta (Ab) production have consistently failed. Alternative approaches are urgently needed. We demon- strated that partial inhibition of mitochondrial complex I with small molecule CP2 induced neuroprotection in multiple mouse models of familial AD. While inhibition of complex I activity has been linked to prolonged lon- gevity, we were the first to show that this approach could be beneficial for AD. CP2 penetrates the blood brain barrier, and accumulates in mitochondria where it competes with the flavin mononucleotide for binding to the redox center of complex I. Partial inhibition of complex I activity induced beneficial cellular adaptation to oxida- tive stress and enhancement of cellular energetics, which was associated with a significant delay in the devel- opment of cognitive and behavior phenotypes when independent groups of AD mice were treated at pre- or symptomatic stages of the disease. However, along with the benefits of treatment that included a reduction of soluble and insoluble Ab and pTau, inhibition of glycogen synthase kinase 3b activity, restoration of axonal traf- ficking and levels of brain-derived neurotrophic factor and synaptic proteins, CP2 induced activation of AMP activated protein kinase (AMPK). Taken into consideration detrimental effects reported in relation to the AMPK activation in humans, to achieve efficacious and safe therapeutic response using mitochondrial complex I in- hibitors in the context of AD, it is imperative to understand the molecular mechanisms to avoid failure in trans- lating our findings into clinical settings. The specific experimental goals are: 1) to test the central hypothesis that activation of AMPK is not required for CP2-induced neuroprotection; 2) to determine the hierarchy of mo- lecular mechanisms other than AMPK activation involved in neuroprotection; 3) to confirm these mechanisms in mouse models of AD that express both human Aβ and Tau protein (3xTgAD) and ApoE4 knock in mice that resemble sporadic AD; 4) to establish blood-based biomarkers for target engagement for translational studies; 5) to determine translational potential of this approach in human neuronal cells; and 6) to conduct phar- macogenomics study using lymphoblastoid cell lines from diverse healthy population to establish safety mar- gins and individualized response to treatment. The proposed studies will provide a rigorous evaluation of molecular mechanisms essential for CP2 neuropro- tection and will investigate the translational potential and safety of this approach for AD using targeted genetic perturbations and advanced techniques in multiple mouse and human model systems. The outcomes will justi- fy the development of combination therapy to mitigate potentially harmful side effects, and biomarkers to moni- tor target engagement and safety. Since the majority of experiments will be conducted in parallel with metfor- min, the only complex I inhibitor that is FDA approved to treat diabetes, the outcomes will also provide the criti- cal biological evidence to establish the rationale and the preclinical criteria, to support further clinical develop- ment of specific MCI inhibitors for AD treatment. ! ! !