Diet and Exercise (DE) Program for Alzheimer Prevention

描述（由申请人提供）：本申请直接针对三个挑战领域：第一个广泛的挑战领域（01）行为、行为改变和预防（专题01- ag -102神经机制），第二个广泛的挑战领域（03）生物标志物的发现和验证（专题03- ag -111桥动物模型），第三个广泛的挑战领域（05）比较有效性研究（专题05- ag -105*疾病和衰老综合征包括神经退行性疾病”）。我们将使用两种不同类型的动物模型来评估饮食和运动结合模式（DE）对生物标志物和认知的潜在影响，这些动物模型用于年龄相关的阿尔茨海默病（AD）淀粉样蛋白和tau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联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。阿尔茨海默病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，因此需要一种副作用和成本问题最小的阿尔茨海默病预防计划。挑战1)多种途径似乎有助于AD的进展。由于阿尔茨海默病的发病机制很复杂，不同的阶段和病理同时发生在不同的大脑区域，为了达到最佳效果，可能需要单独的治疗组合。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，以AD的发病机制为目标，并可能限制其他与年龄相关的病理。挑战2)单一的AD模型不足。大多数提出的AD治疗仅针对A¿或tau蛋白，并且大多数在不完整AD模型（通常仅针对A¿）的病变之前应用。因此，我们建议使用双重模型：一种评估-淀粉样蛋白(A)依赖性认知退化，另一种评估tau依赖性认知退化和神经变性。挑战3)应该确定模型中的生物标志物，以预测试验中的临床变化。因此，我们将采用转基因大鼠模型，我们已经证明神经成像和脑脊液生物标志物可以很容易地跟踪（目的1）。我们的数据表明，在APP/ A¿和tau病理模型中，omega-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）协同作用可减少AD的发病机制。在非ad模型中，DHA和运动之间的协同作用已得到证实。因此，我们提出了一个联合治疗方案，以测试饮食（DHA，姜黄素）和运动干预。由于阿尔茨海默病没有理想的模型，我们建议使用分离淀粉样斑块（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）两种模型。测量的变量将包括认知功能、突触标记物、淀粉样PET成像以及阿尔茨海默氏症的脑脊液和血浆生物标记物。阿尔茨海默病是一种毁灭性的老年疾病——预计将导致50万亿美元的医疗保险赤字，需要大幅增加税收或失去医疗福利，因为7500万婴儿潮一代导致我们的人口老龄化。新药和高技术干预措施（基因或干细胞治疗）可能非常昂贵，有副作用，可能适合治疗，但不太可能是可行的预防方法。基于初步成功的证据，该项目旨在开发一种廉价、安全、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身上的疗效有可能在临床中得到快速评估，使用替代的“生物标志物”来治疗疗效。

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.