Diet and Exercise (DE) Program for Alzheimer Prevention

描述（由申请人提供）：本申请直接涉及三个挑战领域：第一个广泛的挑战领域（01）行为，行为改变和预防（特定主题01-AG-102神经机制），第二大挑战领域（03）生物标志物发现和验证（特定主题03-AG-111桥梁动物模型）和第三大挑战领域（05）比较有效性研究（特定主题“05-AG-105* 包括神经退行性疾病在内的衰老疾病和并发症”）。我们将使用两种不同类型的动物模型评估饮食和运动相结合的模式（DE）对生物标志物和认知的潜在影响，用于年龄相关的阿尔茨海默病（AD）淀粉样蛋白和tau蛋白病理学以及相关的神经变性。所描述的实验将定义这些治疗或组合治疗如何影响认知、神经元和突触蛋白以及CSF生物标志物的改变。AD是痴呆症最常见的原因，随着人口老龄化，预计将迅速耗尽医疗保险，这就需要一个副作用和成本问题最小的AD预防计划。挑战1）多种途径似乎有助于AD进展。由于AD的发病机制是复杂的，不同的阶段和病理同时发生在不同的大脑区域，个别治疗可能必须组合以获得最佳结果。我们的数据表明，DE组分以多种方式协同作用，以限制淀粉样蛋白（斑块）和tau（缠结）病理学以及相关的氧化损伤和炎症。因此，我们建议开发一种优化的联合治疗方案，该方案针对AD发病机制，也可能限制其他年龄相关的病理。挑战2）AD的单一模型不足。大多数提出的AD治疗仅针对A？或tau，并且大多数已在不完全AD模型中的病变之前应用，通常仅针对A？的模型。因此，我们建议使用双重模型：一个评估淀粉样蛋白（A）依赖性认知恶化，另一个评估tau依赖性认知恶化和神经退行性变。挑战3）模型中的生物标志物应该被识别，可以预测临床试验的变化。因此，我们将采用转基因大鼠模型，其中我们已经证明可以容易地跟踪神经成像和CSF生物标志物（目的1）。我们的数据表明，ω-3脂肪酸二十二碳六烯酸（DHA）和酚类抗氧化剂姜黄素（来自姜黄）协同作用，以减少APP/ A？和tau病理模型中的AD发病机制。在非AD模型中，DHA和运动之间的协同作用已经得到证实。因此，我们提出了一个联合治疗计划，以测试饮食（DHA，姜黄素）和运动干预。由于没有理想的AD模型，我们建议使用两种模型，分离淀粉样蛋白斑块（Aim 1，转基因APP/PS1大鼠模型）或缠结/神经元丢失（Aim 2，野生型人tau模型）。测量的变量将是认知功能、突触标志物、淀粉样蛋白PET成像以及AD的可获得CSF和血浆生物标志物。阿尔茨海默病是老龄化的毁灭性疾病之一-预计将导致50万亿美元的医疗保险赤字，需要大规模增税或医疗福利损失，因为7500万婴儿潮一代导致我们的人口老龄化。新药物和高技术干预（基因或干细胞疗法）可能非常昂贵，并伴有副作用，可能适合于治疗，但不太可能是可行的预防方法。基于初步证据表明成功，该项目旨在开发一种廉价，安全和有效的预防方法，将非处方膳食补充剂与运动相结合，以预防阿尔茨海默氏症，并表明我们的方法在人们中的疗效有可能在临床上快速评估，使用替代“生物标志物”进行治疗疗效。

DESCRIPTION (provided by applicant): This application directly addresses three challenge areas: first broad Challenge Area (01) Behavior, Behavioral Change, and Prevention (specific topic 01-AG-102 Neural mechanisms), second broad Challenge area (03) Biomarker Discovery and Validation (specific topic 03-AG-111 bridge animal model) and third broad Challenge area (05) Comparative Effectiveness Research (specific topic "05-AG-105* Diseases and Syndromes of Aging Including Neurodegenerative Diseases"). We will evaluate the potential impact on biomarkers and cognition of a combined dietary and exercise paradigm (DE), using two different types of animal models for age-related Alzheimer's disease (AD) amyloid and tau pathology and related neurodegeneration. The experiments described will define how these treatments or combined treatments impact cognition, neuronal and synaptic proteins and alterations in CSF biomarkers. AD, the most common cause of dementia, is projected to rapidly deplete Medicare as our population ages, arguing for the need of an AD prevention program with minimal adverse side-effects and cost issues. Challenge 1) Multiple pathways appear to contribute to AD progression. Because AD pathogenesis is complex with different stages and pathologies occurring in different brain regions simultaneously, individual treatments may have to be combined for optimal results. Our data suggest that the DE components proposed synergize in multiple ways to limit both the ¿-amyloid (plaque) and tau (tangle) pathology and associated oxidative damage and inflammation. Thus we propose to develop an optimized combined therapy program, which targets AD pathogenesis and may also limit other age-related pathologies. Challenge 2) Single models for AD are inadequate. Most proposed AD treatments target only A¿ or tau and most have been applied prior to lesions in incomplete AD models, typically models only for A¿. Thus we propose to use dual models: one that evaluates ¿-amyloid (A¿) dependent cognitive deterioration and one that evaluates tau- dependent cognitive deterioration and neurodegeneration. Challenge 3) Biomarkers in models should be identified that can predict clinical change in trials. Thus we will employ a transgenic rat model where we have demonstrated that neuroimaging and CSF biomarkers can be readily tracked (Aim 1). Our data suggest that the omega-3 fatty acid docosahexaenoic acid (DHA) and the phenolic antioxidant curcumin (from turmeric) synergize to reduce AD pathogenesis in both APP/ A¿ and tau pathology models. In non-AD models, synergism between DHA and exercise has been demonstrated. Therefore we propose a combined therapy program to test dietary (DHA, curcumin) and exercise interventions. Because there are no ideal models for AD, we propose to use two models that isolate amyloid plaque (Aim 1, a transgenic APP/PS1 rat model) or tangle/ neuron loss (Aim 2, wildtype human tau model). Variables measured will be cognitive function, synaptic markers, amyloid PET imaging as well as accessible CSF and plasma biomarkers for AD. h Alzheimer's Disease is one of the devastating diseases of aging - projected to cause a $50 trillion Medicare deficit, requiring a massive tax increase or loss of healthcare benefits, as 75 million baby boomers cause our population to age. New drugs and high technological interventions (gene or stem cell therapy) are likely to be very expensive, associated with side-effects may be appropriate for therapy, but are unlikely to be viable approached for prevention. Based on preliminary evidence indicating success, this project aims to develop a cheap, safe and effective prevention method with over the counter dietary supplements combined with exercise to prevent Alzheimer's and to show that efficacy with our approach in people has the potential to be quickly evaluated in the clinic, using surrogate "biomarkers" for treatment efficacy.