Mitochondrial Molecules as Therapeutic Drugs for Alzheimer's Disease

线粒体分子作为阿尔茨海默病的治疗药物

• 批准号: 10374919
• 负责人: P. Hemachandra Reddy
• 金额: $ 65.11万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374919
• 关键词: Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Antioxidants; Applications Grants; Area; Autopsy; Behavior; Beta Carotene; Biology; Blood - brain barrier anatomy; Brain; Cardiolipins; Cell Culture Techniques; Cell Survival; Cell model; Cells; Clinical; Clinical Trials; Cognitive; Combined Modality Therapy; Complementary DNA; Complex; Data; Defect; Dendritic Spines; Disease Progression; Drug Kinetics; Electron Transport; Equilibrium; Functional disorder; Funding; Gene Expression; Goals; Golgi Apparatus; Grant; Guanosine Triphosphate Phosphohydrolases; Impairment; Knock-in Mouse; Length; Measures; Melatonin; Methods; Mitochondria; Morphology; Motor; Mus; Neurodegenerative Disorders; Neurons; Outcome; Oxidative Stress; Pathogenesis; Pathology; Pharmaceutical Preparations; Preventive; Production; Proteins; Reactive Oxygen Species; Reporting; Research; Research Personnel; Respiration; Rodent Model; Senile Plaques; Specimen; Stains; Study models; Synapses; Therapeutic; Toxic effect; Transmission Electron Microscopy; Wild Type Mouse; base; blood-brain barrier crossing; brain tissue; experimental study; inhibitor; mitochondrial dysfunction; mouse model; mutant; pre-clinical; preclinical study; prevent; protective effect; receptor; small molecule; success; tau Proteins; tau aggregation; tau-1; therapeutic development

The objective of this application is to better understand the beneficial effects of the mitochondria (mt)-targeted small molecule SS31 and the mt division inhibitor 1 (Mdivi-1) in Alzheimer’s disease (AD) mouse models. Several lines of evidence suggest that age- and amyloid beta (Aβ)-induced reactive oxygen species (ROS) is associated with mt and synaptic damage in AD. Several studies, including preliminary studies on which the proposed research is in large part based, found that, in postmortem AD brain specimens and brain tissues from AD mice, Aβ is associated with mt and increased levels of ROS production and mt dysfunction, suggesting that Aβ may be a key factor in mt dysfunction and neuronal damage. Based on these observations, targeting mt ROS may be an important therapeutic approach to slowing AD progression. However, clinical trials of AD patients to determine the capability of natural antioxidant-based drugs (natural antioxidants, including VitC, VitE, beta-carotene, and melatonin) to slow disease progression yielded limited success. That research did reveal critical information: that natural antioxidants are not capable of crossing the blood brain barrier and are not capable of reaching critical brain areas affected by AD and so cannot protect mt and synapses in those areas. To overcome this challenge, mt-targeted molecule SS31 was developed and has been proven to cross the blood brain barrier in mouse models of neurodegenerative diseases. However, its efficacies have not been studied preclinically in AD mouse models and clinically in AD patients. Further, in other studies of AD disease progression, defective mt dynamics (increased fission and decreased fusion) were found in AD neurons. Results from others and our preliminary studies revealed that the fission protein Drp1 interacts with Aβ and phosphorylated tau, resulting in excessive mt fragmentation, increased ROS production, defective transport of mt to synapses, low synaptic ATP, and synaptic dysfunction. Preliminary high throughput studies found that mt division inhibitor Mdivi1 reduces excessive mt fragmentation and increases mt fusion in cell models of AD, suggesting that Mdivi1 is a promising drug to treat AD. The objective of our R01 application is to determine protective effects of SS31 (Aim 1), Mdivi-1 (Aim 2), and SS31+Mdivi1 (Aim 3) in APP-KI and tau-Tg mouse models of AD and non-transgenic WT mice, at 2 stages (preventive and curative) of disease progression. Using state-of-the-art methods, mt structural and functional changes, Aβ and tau pathologies, and synaptic alterations will be studied in SS31-, Mdivi1-, SS31+Mdivi1-treated and untreated APP-KI and tau-Tg mice and non-transgenic WT mice. The outcome of the proposed research will take researchers closer to developing therapeutic approaches capable of slowing AD progression – and, ultimately, of curing AD.

本申请的目的是更好地理解线粒体（mt）靶向小分子SS 31和mt分裂抑制剂1（Mdivi-1）在阿尔茨海默病（AD）小鼠中的有益作用 模型一些证据表明，年龄和β淀粉样蛋白（Aβ）诱导的活性氧簇 (ROS)与AD中的线粒体和突触损伤有关。若干研究，包括关于下列问题的初步研究： 这项研究在很大程度上是基于，发现，在死后AD脑标本和大脑中， 从AD小鼠的组织中，Aβ与mt以及ROS产生水平增加和mt功能障碍相关， 提示Aβ可能是mt功能障碍和神经元损伤的关键因素。根据这些观察， 靶向mt ROS可能是减缓AD进展的重要治疗方法。但临床 对AD患者进行试验以确定基于天然抗氧化剂的药物（天然抗氧化剂， 包括维生素C、维生素E、β-胡萝卜素和褪黑激素）减缓疾病进展的效果有限。的 研究确实揭示了重要的信息：天然抗氧化剂不能穿过血脑， 屏障，不能到达受AD影响的关键脑区，因此不能保护mt， 这些区域的突触为了克服这一挑战，开发了MT靶向分子SS 31， 在神经退行性疾病的小鼠模型中被证明可以穿过血脑屏障。但其 尚未在AD小鼠模型和AD患者中进行临床前研究。进一步 AD疾病进展的其他研究，缺陷的mt动力学（增加裂变和减少融合）， 发现于AD神经元。其他人的结果和我们的初步研究表明，分裂蛋白Drp 1 与Aβ和磷酸化tau相互作用，导致mt过度断裂，ROS产生增加， mt向突触的转运缺陷、低突触ATP和突触功能障碍。初步高通量 研究发现，mt分裂抑制剂Mdivi 1减少了mt的过度断裂，并增加了mt的融合， AD细胞模型，表明Mdivi 1是一种有前途的治疗AD的药物。我们的R 01应用程序的目标 确定SS 31（Aim 1）、Mdivi-1（Aim 2）和SS 31 + Mdivi 1（Aim 3）在APP-KI中的保护作用， AD和非转基因WT小鼠的tau-Tg小鼠模型，处于疾病的2个阶段（预防和治愈） 进展使用最先进的方法，mt结构和功能变化，Aβ和tau病理， 将在SS 31-、Mdivi 1-、SS 31 + Mdivi 1-处理和未处理的APP-KI和tau-Tg中研究突触改变 小鼠和非转基因WT小鼠。拟议研究的结果将使研究人员更接近 开发能够减缓AD进展的治疗方法，并最终治愈AD。