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

2016年，世界卫生组织通过了《老龄与健康全球战略和行动计划》，优先考虑和认识世界各地迅速老龄化人口的需求。阿尔茨海默病(AD)是与衰老相关的最重要的疾病指征之一。以认知、记忆、思维、语言和学习能力进行性下降为特征，65岁或以上的人患阿尔茨海默病的风险大幅增加。然而，AD的发展被认为发生在几十年的时间里。AD的病理包括脑脊液(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，这促使研究人员和医疗保健提供者开发和测试对抗AD的新方法。在观察性研究中，使用营养等生活方式因素来缓解与年龄相关的认知障碍是有希望的。2.在前瞻性队列研究中，富含水果和蔬菜的饮食与AD 3的风险降低和认知能力下降有关4。特别是，富含蔬菜、水果、全谷物、坚果和豆类的地中海饮食(MEDI)显示出对神经退化的保护作用5。在认知正常的老年人中，与那些坚持较高的饮食相比，较低的Medi坚持与脑病理、萎缩和葡萄糖代谢不足等AD标记物的增加有关。在另一项研究中，在一组健康女性中没有发现坚持服用MEDI和淀粉样蛋白沉积之间的相关性。使用MEDI治疗AD的临床试验有限，但目前有8项临床试验正在筹备中。相反，食用西式饮食(包括大量精制碳水化合物、红色/加工肉类和高脂肪乳制品)与AD 8相关的不良结局有关。尽管此类研究表明饮食与AD风险之间的关联是显而易见的，但这些观察结果没有外推到针对AD的精确和可行的营养方案开发中，这使得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群，减少炎症和增强细胞应激反应途径10。Medi也可能是核黄素的丰富来源，它们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，可以被MEDI调控的特定分子靶点尚未确定，这对综合利用MEDI作为AD预防工具构成了挑战。因此，我们建议使用5XFAD小鼠来研究Medi在AD中的预防作用，在5XFAD小鼠中，动物过表达突变的人类淀粉样前体蛋白(App1)和早老素1(PSEN1)。我们的假设是，服用Medi的小鼠比服用标准饮食(StDi)和WEDI的小鼠表现出更好的AD结果。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、设计和预期结果： 目的1：确定与STDi相比，MEDI是否预防和WEDI加重AD相关结局。 目的：评价细胞保护的基因操作是否能改变5XFAD小鼠的AD相关结局。 我们现在已经完成了这项研究的第一阶段，目前正在开始脑组织切片和编译手稿的生理数据。 1.萨克斯、C.A.、J.Avorn和A.S.Kesselheim，Solanezumab的失败--FDA如何为纳税人节省了数十亿美元。N Engl J Med，2017。376(18)：第1706-1708页。 2.Scarmeas，N.，C.A.Anastasiou和M.Yannakoulia，《营养与预防认知障碍》。《柳叶刀·神经》，2018年。 3.Gu，Y.等人，地中海饮食，炎症和代谢生物标记物，以及阿尔茨海默病的风险。阿尔茨海默氏症杂志，2010年。22(2)：第483-92页。 4.Kang，J.H.，A.Ascherio，和F.Grodstein，水果和蔬菜消费与老年女性认知能力下降。安·尼罗尔，2005年。57(5)：第713-20页。 5.Gardener，H.和M.R.Cunca，地中海饮食预防神经退行性疾病。Curr Nutr Rep，2018年7(1)：第10-20页。 6.Berti，V.等人，地中海饮食和中年人阿尔茨海默病脑生物标记物的3年变化。神经病学，2018年。90(20)：e1789-e1798页。 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阿尔茨海默氏症，2018年。5(2)：第137-141页。 8.Nicolia，V.，M.Lucarelli和A.Fuso，环境，表观遗传学和神经退化：关注阿尔茨海默病的营养。Exp Gerontol，2015年。68：第8-12页。 9.ThamBisetty，M.，《了解阿尔茨海默氏症的机制和寻求治疗方法：为什么我们必须“异常多样化”“。Am J Physiol Cell Physiol，2017。313(4)：C353-C361页。 10.Martucci，M.等人，地中海饮食和兴奋范式中的炎症。Nutr Rev，2017年。75(6)：第442-455页。

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.