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: 8326042
• 负责人: Jeffrey Neil Keller
• 金额: $ 22.2万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326042
• 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?

描述（由申请人提供）：疾病控制和预防中心估计，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）。新出现的数据有力地表明，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增长的研究领域，旨在绘制饮食脂肪和过度肥胖对大脑的影响，特别是在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，增加的肥胖，特别是内脏肥胖，增加了血管性痴呆和阿尔茨海默病（AD）的风险。此外，来自我们实验室和其他实验室的数据已经清楚地表明，啮齿动物中饮食诱导的肥胖会引起多种神经系统障碍，包括认知障碍和氧化应激标志物增加。所有这些数据都指出HFD和内脏肥胖作为Abeta相关痴呆的潜在重要临床调节剂的重要作用。然而，目前膳食脂肪和肥胖调节脑中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：饮食诱导的肥胖促进Abeta病理学的改变，以及Abeta发病机制的下游组分的相应增加，其部分依赖于内脏肥胖的增加。其次，该提案将检验内脏肥胖水平增加足以促进Abeta病理学以及Abeta发病机制的下游组分的假设。因此，该提案旨在解决（首次）内脏肥胖增加是否是HFD/肥胖诱导的大脑效应所必需的关键问题，以及解决内脏肥胖增加是否足以增加大脑发病机制。 实验的重点将是Abeta病理学的调制，以及Abeta病理学的后果，使用脑淀粉样血管病（CAA）的小鼠模型。选择CAA用于这些研究，因为它既是血管性痴呆的病理学底物，也是AD脑内的常见共同病理学（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批量化措施。内脏肥胖增加是否是饮食诱导的肥胖促进Abeta病理所必需的？内脏脂肪增多是否足以引起Abeta病理改变？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？