Dietary and Visceral Fat Regulate Vascular Amyloid Pathogenesis

膳食和内脏脂肪调节血管淀粉样蛋白的发病机制

• 批准号: 8245332
• 负责人: Jeffrey Neil Keller
• 金额: $ 18.5万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245332
• 关键词: Accounting; Address; Adipose tissue; Age; Aging; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Area; Attenuated; Behavioral; Blood Vessels; Brain; Brain Injuries; Centers for Disease Control and Prevention (U.S.); Cerebral Amyloid Angiopathy; Chronic; Clinical; Consumption; Data; Dementia; Diet; Dietary Fats; Disease; Epidemiologic Studies; Excision; Fatty acid glycerol esters; Functional disorder; Future Generations; Impaired cognition; Incidence; Individual; Laboratories; Lipectomy; Maps; Measures; Metabolism; Molecular; Mus; Neurologic; Obesity; Operative Surgical Procedures; Overweight; Oxidative Stress; Pathogenesis; Pathology; Population; Recording of previous events; Research Design; Risk; Rodent; Role; Severities; Synapses; Testing; Time; Transplantation; Vascular Dementia; Visceral; age related; cerebrovascular; design; dietary excess; disorder prevention; indexing; mouse model; neurobehavior; neurochemistry

DESCRIPTION (provided by applicant): The Centers for Disease Control and Prevention estimates that nearly two thirds of the American population is either overweight or obese, due in part to a chronic consumption of a high fat diet (HFD). Emerging data strongly suggests that the brain is sensitive to the detrimental effects of excessive adiposity. These observations have led to a rapidly growing area of research designed to map the influence of dietary fat and excess adiposity on the brain, particularly in regards to the onset and progression of age-related dementias. For example, recent epidemiological studies suggest that increased adiposity, and specifically visceral adiposity, elevates the risk of both vascular dementia and Alzheimer's disease (AD). Furthermore, data from our laboratory and others have clearly demonstrated that diet-induced adiposity in rodents elicits multiple neurologic disturbances including cognitive impairment and increased markers of oxidative stress. All of these data point to a significant role for HFD and visceral adiposity as potentially important clinical modulators of Abeta- associated dementias. However, at present the extent to which, and the mechanisms by which, dietary fat and adiposity regulate Abeta pathogenesis in the brain is not yet known. This proposal will test the hypothesis that dietary induced obesity promotes alterations in Abeta pathology, and corresponding increases in the downstream components of Abeta pathogenesis, that are dependent in part on increases in visceral adiposity. Secondly, this proposal will test the hypothesis that increased levels of visceral adiposity are sufficient to promote Abeta pathology, and the downstream components of Abeta pathogenesis. This proposal is therefore designed to address (for the first time) the critical questions as to whether increased visceral adiposity is necessary for HFD/obesity-induced effects on the brain, as well as address whether increased visceral adiposity is sufficient to increase brain pathogenesis. The focus of experimentation will be on the modulation of Abeta pathology, and the consequences of Abeta pathology, using a mouse model of cerebral amyloid angiopathy (CAA). CAA was selected for these studies since it is both a pathological substrate for vascular dementia, as well as a common co-pathology within the AD brain (present in ~80% of AD cases). These studies will comprehensively analyze the continuum of Abeta pathogenesis in the context of changes in adiposity, metabolism, neurobehavior, and neurochemistry. Completion of the proposed studies will provide the first quantitative measures on each of the following questions. Is increased visceral adiposity necessary for dietary induced obesity promotion of Abeta pathology? Is increased visceral adiposity sufficient to induce alterations in Abeta pathology? How do these effects of visceral adiposity towards Abeta pathology relate to specific behavioral and molecular indices of brain injury? PUBLIC HEALTH RELEVANCE: Currently 66% of individuals in the US are overweight or obese, due in part to the regular consumption of high fat diets, with the number of Americans over 65 accounting for an ever increasing percentage of the total US population. These realities are unprecedented in American history, and are almost certain to redefine how current and future generations of Americans age, as the interactions between increased adiposity and aging increase the incidence and severity of numerous diseases (including age-related dementias). Studies in this proposal will for the first time define how increased visceral adiposity modulates the neuropathological, neurochemical, and behavioral abnormalities observed in mouse models of beta amyloid pathogenesis.

描述（由申请人提供）：美国疾病控制与预防中心估计，近三分之二的美国人口超重或肥胖，部分原因是长期食用高脂肪饮食 (HFD)。新出现的数据强烈表明，大脑对过度肥胖的有害影响很敏感。这些观察结果导致了一个快速发展的研究领域，旨在绘制膳食脂肪和过度肥胖对大脑的影响，特别是与年龄相关的痴呆症的发病和进展方面。例如，最近的流行病学研究表明，肥胖，特别是内脏肥胖的增加，会增加血管性痴呆和阿尔茨海默病 (AD) 的风险。此外，我们实验室和其他实验室的数据清楚地表明，啮齿类动物饮食引起的肥胖会引起多种神经系统紊乱，包括认知障碍和氧化应激标志物增加。所有这些数据都表明 HFD 和内脏肥胖作为 Abeta 相关痴呆的潜在重要临床调节剂发挥着重要作用。然而，目前膳食脂肪和肥胖在大脑中调节 Abeta 发病机制的程度和机制尚不清楚。该提案将检验以下假设：饮食引起的肥胖会促进 Abeta 病理学的改变，以及 Abeta 发病机制下游成分的相应增加，这部分取决于内脏肥胖的增加。其次，该提案将检验以下假设：内脏肥胖水平的增加足以促进 Abeta 病理学以及 Abeta 发病机制的下游组成部分。因此，该提案旨在（首次）解决以下关键问题：内脏脂肪增加是否是 HFD/肥胖引起的大脑影响所必需的，以及解决内脏脂肪增加是否足以增加大脑发病机制。 实验的重点将是使用脑淀粉样血管病 (CAA) 小鼠模型来调节 Abeta 病理学以及 Abeta 病理学的后果。选择 CAA 进行这些研究是因为它既是血管性痴呆的病理基础，也是 AD 脑内常见的共同病理（存在于约 80% 的 AD 病例中）。这些研究将在肥胖、代谢、神经行为和神经化学变化的背景下全面分析 Abeta 发病机制的连续性。完成拟议的研究将为以下每个问题提供第一个定量测量。饮食诱发的肥胖促进 Abeta 病理学是否需要增加内脏脂肪？内脏脂肪增多是否足以引起 Abeta 病理学的改变？内脏肥胖对 Abeta 病理学的这些影响与脑损伤的特定行为和分子指标有何关系？ 公共健康相关性：目前，美国有 66% 的人超重或肥胖，部分原因是经常食用高脂肪饮食，而且 65 岁以上的美国人占美国总人口的比例不断增加。这些现实在美国历史上是前所未有的，并且几乎肯定会重新定义当前和未来几代美国人的衰老方式，因为肥胖增加和衰老之间的相互作用会增加多种疾病（包括与年龄相关的痴呆症）的发病率和严重程度。该提案中的研究将首次明确内脏肥胖增加如何调节在β淀粉样蛋白发病机制小鼠模型中观察到的神经病理学、神经化学和行为异常。