Dietary and Visceral Fat Regulate Vascular Amyloid Pathogenesis

描述(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，特别是与年龄相关的痴呆的发生和发展。例如，最近的流行病学研究表明，肥胖增加，特别是内脏肥胖，会增加患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清楚地表明，饮食诱导的啮齿动物肥胖会引起多种神经障碍，包括认知障碍和氧化应激标志物的增加。所有这些数据表明，HFD和内脏肥胖症作为Abeta相关痴呆的潜在重要临床调节因子具有重要作用。然而，目前，饮食脂肪和肥胖调节大脑Abeta发病的程度和机制尚不清楚。这项提议将检验这一假设，即饮食诱导的肥胖促进Abeta病理的改变，以及Abeta发病机制下游部分的相应增加，这部分依赖于内脏脂肪的增加。其次，这项提议将检验这样的假设，即内脏脂肪水平的增加足以促进Abeta病理，以及Abeta发病的下游组成部分。因此，这项建议旨在(首次)解决以下关键问题：内脏脂肪增加是否对HFD/肥胖症对大脑的影响是必要的，以及内脏脂肪增加是否足以增加大脑的发病机制。实验的重点将是利用大脑淀粉样血管病变(CAA)的小鼠模型，研究Abeta病理的调节以及Abeta病理的后果。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、新陈代谢、神经行为和神经化学变化的背景下综合分析Abeta发病的连续体。拟议研究的完成将为以下每个问题提供第一批量化措施。内脏脂肪增加对于饮食诱导肥胖促进Abeta病理来说是必要的吗？内脏脂肪增加是否足以引起Abeta病理改变？内脏肥胖对Abeta病理的这些影响与脑损伤的特定行为和分子指标有何关系？

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?