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(Aβ)的生产一直失败。迫切需要其他方法。我们确认了 线粒体复合体I(MCI)是治疗AD的小分子药物靶点。对MCI诱导的部分抑制作用 多方面适应性应激反应激活多家系小鼠模型的神经保护机制 公元后的ELS。认知功能障碍发作后，长期应用MCI抑制剂治疗有效，减少了患者的认知障碍。 ING炎症、氧化应激、Aβ和PTAU，导致突触功能、脑能量学和 认知能力，最终阻止正在进行的神经退化。翻译潜力超乎寻常- 通过交叉验证小鼠数据和来自NIH AMP-AD数据的人类转录数据- 基础，证明了治疗改善了AD小鼠的通路，包括免疫系统恢复 海绵体和神经传递是AD患者治疗效果的关键机制。而当 越来越多的数据表明，通过抑制MCI来诱导轻微的能量应激可以延长寿命， 延长健康寿命，延缓与年龄相关的神经退行性疾病的发病，包括阿尔茨海默病，机制- 对于是什么使得以小分子为靶点的MCI是安全的，缺乏本能的理解。它还有待于 确定这种治疗对迟发性AD(LOAD)患者是否有益，这是最严重的 这种疾病的另一种形式。 这一竞争性更新的目标是利用孤立的MAM进行结构-活性关系研究。 马里MCI，以及一系列生物化学和细胞生物学技术，报告细胞和人类神经元，以及 新的和已建立的MCI抑制剂文库，以确定哪些因素，包括MCI抑制的位置， 结合亲和力、ROS产生的水平和位置以及小分子的结构保证了MCI的安全性 抑制和诱导一种神经保护性信号。接下来，我们将验证新型MCI抑制剂的有效性 在实验室开发并获得专利的3D共培养神经元/星形胶质细胞/小胶质细胞来自于 加载男性和女性患者。最后，治疗效果和分子机制将在 载脂蛋白E4敲入小鼠模型负荷。多组学数据与现有人类代谢的交叉验证， 表观遗传学和转录学数据库将确定男性治疗逆转的特定机制 和女性负载患者，支持这一创新治疗方法的翻译价值。新奇的信息- 将MCI描述为利用分离的哺乳动物产生的小分子药物治疗靶点的信息 MCI和包括冷冻-EM在内的先进技术可以显著推动AD药物发现领域的发展 以及其他疾病。使用人体和动物模型进行的力学研究可能会提供新的证据 线粒体适应性应激反应在神经保护中起着细胞特有的作用。翻译双- 治疗效果的标志物可能有助于未来临床试验的设计。

Alzheimer’s Disease (AD) has no effective treatments, and recent clinical trials focused on preventing of amy- loid beta (Aβ) production have consistently failed. Alternative approaches are urgently needed. We identified mitochondrial complex I (MCI) as a small molecule druggable target for AD. Partial inhibition of MCI induced multifaceted adaptive stress response activating neuroprotective mechanisms in multiple familial mouse mod- els of AD. Chronic treatment with MCI inhibitors was efficacious after the onset of cognitive dysfunction, reduc- ing inflammation, oxidative stress, Aβ and pTau, leading to improved synaptic function, brain energetics, and cognitive performance, ultimately blocking the ongoing neurodegeneration. Translational potential was sup- ported by cross-validation of the mouse data with the human transcriptomic data from the NIH AMP-AD data- base, demonstrating that pathways improved by the treatment in AD mice, including the immune system re- sponse and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients. While mounting data suggest that the induction of mild energetic stress via MCI inhibition could promote longevity, increase health span, and delay the onset of age-related neurodegenerative disease, including AD, the mecha- nistic understanding of what makes targeting of MCI with small molecules safe is lacking. It is also remains to be determined whether this treatment could be beneficial in patients with late onset AD (LOAD), the most prev- alent form of the disease. The objective of this competitive renewal is to conduct structure-activity relationship studies using isolated mam- malian MCI, and array of biochemistry and cell biology techniques, reporter cells and human neurons, and a library of novel and established MCI inhibitors to determine what factors, including the site of MCI inhibition, binding affinity, levels and sites of ROS production, and the structure of small molecules ensure safety of MCI inhibition and the induction of a neuroprotective signaling. We will next validate efficacy of novel MCI inhibitor developed and patented in the lab in 3D co-cultures of neurons/astrocytes/microglia derived from the iPSCs of LOAD male and female patients. Finally, therapeutic efficacy and molecular mechanisms will be confirmed in APOE4 Knock In mouse model of LOAD. Cross-validation of multi-omics data with the existing human metabolic, epigenetic and transcriptomic databases will determine specific mechanisms reversed by the treatment in male and female LOAD patients, supporting translational value of this innovative therapeutic approach. Novel infor- mation delineating MCI as a small molecule druggable therapeutic target generated using isolated mammalian MCI, and advanced techniques, including cryo-EM, could significantly advance the field of drug discovery for AD and other diseases. Mechanistic studies using human and animal models of LOAD could provide novel evidence for the cell-specific role mitochondrial adaptive stress response plays in neuroprotection. Translational bi- omarkers of therapeutic efficacy could aid in the design of future clinical trials.