Mitochondrial Complex I as a Target for Neuroprotection in AD

阿尔茨海默病(AD)目前还没有有效的治疗方法，最近的临床试验主要集中在预防AMY- Loid Beta(Ab)的生产一直失败。迫切需要其他方法。我们是恶魔- 小分子CP2部分抑制线粒体复合体I诱导的神经保护作用 家族性阿尔茨海默病的多种小鼠模型。而抑制复合体I的活性与长时间的Lon- Gevity，我们是第一个证明这种方法可能对AD有益的人。CP2穿透血脑 屏障，并在线粒体中积累，在那里它与黄素单核苷酸竞争结合 络合物I的氧化还原中心。部分抑制络合物I的活性可诱导有益的细胞对氧化的适应。 主动应激和细胞能量学的增强，这与发育的显著延迟有关。 独立AD组小鼠在治疗前的认知和行为表型的变化 疾病的症状阶段。然而，随着治疗的好处，包括减少 可溶性和不溶性抗体和ptau，抑制糖原合成酶3b活性，恢复轴突TRAF-1。 CP2激活AMP与脑源性神经营养因子和突触蛋白水平的关系 活化蛋白激酶(AMPK)。考虑到与AMPK有关的有害影响 在人类中激活，以实现有效和安全的治疗反应使用线粒体复合体I在- 在AD的背景下，了解分子机制以避免反式-TRAN失败是非常必要的。 将我们的发现应用到临床环境中。具体的实验目标是：1)检验中心假说 在CP2诱导的神经保护中，AMPK的激活不是必需的；2)确定运动的层级。 AMPK激活以外的其他机制参与神经保护；3)确认这些机制 在同时表达人Aβ和Tau蛋白(3xTgAD)的AD小鼠模型中，ApoE4敲击小鼠 类似于散发性阿尔茨海默病；4)建立基于血液的生物标记物，用于翻译研究的靶点参与； 5)确定这一方法在人神经细胞中的翻译潜力；6)进行药物筛选。 利用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记 GINS和个体化治疗反应。 建议的研究将提供对CP2神经前体所必需的分子机制的严格评估。 并将使用靶向基因来研究这种方法在AD中的翻译潜力和安全性 多个老鼠和人体模型系统中的扰动和先进技术。结果只会是- 联合治疗的发展，以减轻潜在的有害副作用，以及对Moni的生物标志物。 托尔的目标是交战和安全。由于大多数实验将与Metfor并行进行- MIN是FDA批准用于治疗糖尿病的唯一一种复杂的I类抑制剂，其结果也将提供治疗糖尿病的标准。 CAL生物学证据，以建立理论基础和临床前标准，以支持进一步的临床开发- 应用特异性MCI抑制剂治疗AD。 好了！ 好了！ 好了！

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. ! ! !