Cross-Translational nutritional interventions for Alzheimer's Disease: from man to mouse

阿尔茨海默病的跨转化营养干预：从人到小鼠

• 批准号: 10913039
• 负责人: Rafael de Cabo
• 金额: $ 1.79万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913039
• 关键词: Adherence; Adopted; Adult; Age-associated memory impairment; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid Proteins; Amyloid deposition; Animals; Atrophic; Attenuated; Behavior; Biological Markers; Body Weight; Brain Pathology; Carbohydrates; Cells; Cellular Stress; Cerebrospinal Fluid; Clinical; Clinical Trials; Cognition; Cognitive; Consumption; Cytoprotection; Dairying; Data; Development; Diet; Dietary Fiber; Dietary Intervention; Disease; Disease Marker; Disease Outcome; Elderly; Electrons; Environment; Epigenetic Process; Fabaceae; Failure; Fatty acid glycerol esters; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Fruit; Genes; Glucose; Goals; Health; Health Personnel; Histologic; Human Amyloid Precursor Protein; Impaired cognition; Individual; Inflammaging; Inflammation; Inflammatory; Language; Magnetic Resonance Imaging; Manuscripts; Mediating; Mediterranean Diet; Memory; Metabolic; Methodology; Molecular; Molecular Target; Mus; Mutation; NADP; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurology; Nutritional; Nuts; Observational Study; Outcome; Oxidoreductase; Pathway interactions; Phenotype; Physiological; Plant Components; Population; Prevention; Preventive; Processed Meats; Prospective, cohort study; Quinones; Regimen; Research; Research Personnel; Riboflavin; Role; Senile Plaques; Serum; Source; Testing; Thinking; Time; Vegetables; Weaning; Woman; World Health Organization; abeta deposition; aged; brain tissue; cohort; design; dietary adherence; fruits and vegetables; genetic manipulation; good diet; gut microbiome; healthy aging; learning ability; lifestyle factors; lipidomics; man; metabolomics; middle age; mouse model; mutant; neuron loss; novel; novel strategies; nutrition; overexpression; phase 1 study; presenilin-1; prevent; protein expression; tau Proteins; tool; treatment strategy; western diet

In 2016, the World Health Organization adopted a Global Strategy and Action Plan on Ageing and Health to prioritize and recognize the needs of rapidly aging populations worldwide. Alzheimers disease (AD) is one of the most significant disease indications associated with aging. Characterized by the progressive decline of cognition, memory, thinking, language and learning ability, the risk of AD is substantially increased in individuals aged 65 or above. However, the development of AD has been postulated to occur over several decades. AD pathologies include enhanced levels of amyloid and tau protein in the cerebrospinal fluid (CSF) as well as the formation of senile plaques and neurofibrillary tangles that ultimately contribute to inflammation followed by neuronal death. In spite of many years of research, successful treatment strategies have not yet been identified 1, urging researchers and healthcare providers to develop and test novel approaches against AD. The use of lifestyle factors such as nutrition to mitigate age-related cognitive impairment has shown promise in observational studies 2. In prospective cohort studies, diets rich in fruits and vegetables are associated with reduced risk of AD 3 and lower cognitive decline 4. In particular, the Mediterranean diet (MeDi) that is rich in vegetables, fruits, whole grains, nuts and legumes show protective associations against neurodegeneration 5. In cognitively intact elderly, lower MeDi adherence was associated with increased AD markers such as brain pathology, atrophy and glucose hypometabolism compared to those with higher adherence 6. Interestingly, in another study no correlation was found between adherence to MeDi and -amyloid deposition in a cohort of healthy women 7. Clinical trials employing MeDi against AD are limited but currently there are 8 in the pipeline Clinicaltrials.gov. Conversely, consumption of Western-style diets (WeDi), comprising of large amounts of refined carbohydrates, red/processed meat and high-fat dairy, have been associated with poor outcomes related to AD 8. Although the association between diet and risk of AD are apparent from such studies, the lack of extrapolation of these observations into precise and actionable nutritional regimen development against AD has made such findings clinically futile 9. At the molecular level, plant components of the MeDi can alter the gut microbiome, reduce inflammation and enhance cellular stress response pathways 10. It is also likely that MeDi can act as a rich source of riboflavins, that are precursors to the electron carriers flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). However specific molecular targets that can be modulated by MeDi have not been identified do date posing a challenge to comprehensively utilizing MeDi as an AD prevention tool. Thus, we propose to study the preventive role of MeDi in AD using the 5XFAD mice, where animals overexpress mutant human Amyloid Precursor Protein (App1) and Presenilin 1 (Psen1). Our hypothesis is that mice on MeDi would show better AD outcomes compared to mice on standard diet (StDi) and WeDi. We plan on quantitating these changes using diverse methodologies through the following specific aims. STUDY GOALS, DESIGN AND EXPECTED OUTCOMES: Aim 1: Determine whether MeDi prevents and WeDi exacerbates AD-related outcomes compared to StDi. Aim 2: Evaluate whether genetic manipulation of cytoprotection can alter AD-related outcomes in 5XFAD mice. We have now completed the phase 1 of this study and are currently initiating the sectioning of brain tissue and complying the physiological data for a manuscript. 1. Sacks, C.A., J. Avorn, and A.S. Kesselheim, The Failure of Solanezumab - How the FDA Saved Taxpayers Billions. N Engl J Med, 2017. 376(18): p. 1706-1708. 2. Scarmeas, N., C.A. Anastasiou, and M. Yannakoulia, Nutrition and prevention of cognitive impairment. Lancet Neurol, 2018. 3. Gu, Y., et al., Mediterranean diet, inflammatory and metabolic biomarkers, and risk of Alzheimer's disease. J Alzheimers Dis, 2010. 22(2): p. 483-92. 4. Kang, J.H., A.Ascherio, and F. Grodstein, Fruit and vegetable consumption and cognitive decline in aging women. Ann Neurol, 2005. 57(5): p. 713-20. 5. Gardener, H. and M.R. Caunca, Mediterranean Diet in Preventing Neurodegenerative Diseases. Curr Nutr Rep, 2018. 7(1): p. 10-20. 6. Berti, V., et al., Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology, 2018. 90(20): p. e1789-e1798. 7. Hill, E., et al., Adherence to the Mediterranean Diet Is not Related to Beta-Amyloid Deposition: Data from the Women's Healthy Ageing Project. J Prev Alzheimers Dis, 2018. 5(2): p. 137-141. 8. Nicolia, V., M. Lucarelli, and A. Fuso, Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease. Exp Gerontol, 2015. 68: p. 8-12. 9. Thambisetty, M., Understanding mechanisms and seeking cures for Alzheimer's disease: why we must be "extraordinarily diverse". Am J Physiol Cell Physiol, 2017. 313(4): p. C353-C361. 10. Martucci, M., et al., Mediterranean diet and inflammaging within the hormesis paradigm. Nutr Rev, 2017. 75(6): p. 442-455.

2016年，世界卫生组织通过了《老龄化与健康全球战略和行动计划》，优先考虑并认识到全球人口迅速老龄化的需求。阿尔茨海默病（AD）是与衰老相关的最重要的疾病适应症之一。 65岁或以上人士以认知、记忆、思维、语言及学习能力进行性衰退为特征，罹患AD的风险显着增加。然而，AD 的发展被认为需要几十年的时间。 AD 病理包括脑脊液 (CSF) 中淀粉样蛋白和 tau 蛋白水平升高，以及老年斑和神经原纤维缠结的形成，最终导致炎症和神经元死亡。尽管进行了多年的研究，但尚未确定成功的治疗策略1，这敦促研究人员和医疗保健提供者开发和测试针对 AD 的新方法。利用营养等生活方式因素来减轻与年龄相关的认知障碍已在观察性研究中显示出希望 2。在前瞻性队列研究中，富含水果和蔬菜的饮食与降低 AD 风险相关 3 和认知能力下降 4。富含蔬菜、水果、全谷物、坚果和豆类的地中海饮食 (MeDi) 对神经退行性变具有保护作用 5。在认知能力完好的老年人中，较低的 Medi 依从性与 AD 标志物（如脑部病理学、萎缩）的增加有关6. 有趣的是，在另一项研究中，在一组健康女性中，没有发现 MeDi 的依从性与淀粉样蛋白沉积之间存在相关性 7. 使用 MeDi 治疗 AD 的临床试验有限，但目前有 8 项管道临床试验.gov。相反，食用含有大量精制碳水化合物、红肉/加工肉和高脂乳制品的西式饮食 (WeDi) 与 AD 8 相关的不良结局有关。尽管饮食与 AD 风险之间存在关联从这些研究中可以明显看出，由于缺乏将这些观察结果推断为针对 AD 的精确且可操作的营养方案开发，因此这些发现在临床上是徒劳的 9。在分子水平上，Medi 的植物成分可以改变肠道微生物组，减少炎症并增强细胞应激反应途径 10. MeDi 也可能作为核黄素的丰富来源，核黄素是电子载体黄素腺嘌呤二核苷酸 (FAD) 和黄素单核苷酸 (FMN) 的前体。然而，迄今为止，尚未确定 MeDi 可以调节的特定分子靶标，这对全面利用 MeDi 作为 AD 预防工具提出了挑战。因此，我们建议使用 5XFAD 小鼠研究 MeDi 在 AD 中的预防作用，这些小鼠过度表达突变型人类淀粉样前体蛋白 (App1) 和早老素 1 (Psen1)。我们的假设是，与使用标准饮食 (StDi) 和 WeDi 的小鼠相比，使用 MeDi 的小鼠会表现出更好的 AD 结局。我们计划通过以下具体目标使用不同的方法来量化这些变化。 研究目标、设计和预期成果： 目标 1：确定与 StDi 相比，MeDi 是否可以预防 AD 相关后果，而 WeDi 是否会加剧 AD 相关后果。 目标 2：评估细胞保护的基因操作是否可以改变 5XFAD 小鼠的 AD 相关结果。 我们现已完成这项研究的第一阶段，目前正在启动脑组织切片并遵守手稿的生理数据。 1. Sacks、C.A.、J. Avorn 和 A.S. Kesselheim，Solanezumab 的失败 - FDA 如何为纳税人节省数十亿美元。新英格兰医学杂志，2017。376（18）：p。 1706-1708。 2. 北卡罗来纳州斯卡米斯Anastasiou 和 M. Yannakoulia，营养与认知障碍的预防。柳叶刀神经醇，2018。 3. Gu, Y., et al.，地中海饮食、炎症和代谢生物标志物以及阿尔茨海默氏病的风险。 《阿尔茨海默病杂志》，2010。22(2)：第 17 页。 483-92。 4. Kang, J.H., A.Ascherio, 和 F. Grodstein，老年女性的水果和蔬菜消费与认知能力下降。安·尼罗尔，2005 年。57(5)：第 17 页。 713-20。 5. Gardener, H. 和 M.R. Caunca，《地中海饮食预防神经退行性疾病》。当前营养报告，2018。7(1)：第 17 页。 10-20。 6. Berti, V. 等人，地中海饮食和中年成人 3 年阿尔茨海默病大脑生物标志物变化。神经病学，2018。90（20）：p。 e1789-e1798。 7. Hill, E. 等人，坚持地中海饮食与 β-淀粉样蛋白沉积无关：来自妇女健康老龄化项目的数据。 J Prev 阿尔茨海默病，2018。5(2)：p。 137-141。 8. Nicolia, V.、M. Lucarelli 和 A. Fuso，《环境、表观遗传学和神经变性：关注阿尔茨海默病的营养》。 Exp Gerontol，2015。68：p。 8-12。 9. Thambisetty, M.，了解阿尔茨海默病的机制并寻求治疗方法：为什么我们必须“极其多样化”。 Am J Physiol Cell Physiol，2017。313（4）：p。 C353-C361。 10. Martucci, M. 等人，地中海饮食和毒物兴奋效应范式内的炎症。 《营养评论》，2017 年。75(6)：第 75 页。 442-455。