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：第一大挑战领域(01)行为、行为变化和预防(特定主题01-AG-102神经机制)，第二大挑战领域(03)生物标记物发现和验证(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老龄化的疾病和综合征”)。我们将使用两种不同类型的老年性阿尔茨海默病(AD)淀粉样蛋白和tau病理及相关神经变性的动物模型，评估饮食和运动相结合的范例(DE)对生物标志物和认知的潜在影响。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脑脊液生物标记物的变化。AD是导致痴呆症的最常见原因，随着我们人口的老龄化，预计它将迅速耗尽医疗保险，因此需要一个副作用和成本问题最小的AD预防计划。挑战1)多条途径似乎有助于AD的进展。由于阿尔茨海默病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，因此可能必须联合使用单独的治疗方法才能获得最佳效果。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的发病机制，也可能限制其他与年龄相关的病理。挑战2)AD的单一模型是不够的。大多数建议的AD治疗只针对A？或tau，而且大多数都是在不完全AD模型病变之前应用的，通常只针对A？模型。因此，我们建议使用双重模型：一种评估依赖淀粉样蛋白(A)的认知退化，另一种评估依赖tau的认知退化和神经退化。挑战3)模型中的生物标记物应该能够预测试验中的临床变化。因此，我们将使用转基因大鼠模型，在那里我们已经证明了神经成像和脑脊液生物标记物可以很容易地被追踪(目标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，可以减少AD的发病。在非AD模型中，DHA和运动之间的协同作用已被证明。因此，我们提出了一种综合治疗方案，以测试饮食(DHA、姜黄素)和运动干预。由于没有理想的AD模型，我们建议使用两种分离淀粉样斑块的模型(Aim 1，转基因APP/PS1大鼠模型)或缠结/神经元丢失(Aim 2，野生型人类tau模型)。测量的变量包括认知功能、突触标志物、淀粉样蛋白PET成像以及AD的可及脑脊液和血浆生物标志物。阿尔茨海默氏症是一种毁灭性的老龄化疾病-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。新药和高科技干预措施(基因或干细胞疗法)可能非常昂贵，与副作用相关，可能适合用于治疗，但不太可能可行地进行预防。基于成功的初步证据，该项目旨在开发一种廉价、安全和有效的预防方法，将非处方药膳食补充剂与运动相结合来预防阿尔茨海默氏症，并表明我们的方法在人们中的有效性有可能在临床上得到快速评估，使用替代治疗效果的“生物标记物”。

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.