Dietary and Visceral Fat Regulate Vascular Amyloid Pathogenesis

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发展的研究领域，旨在绘制膳食脂肪和过量脂肪对大脑的影响，特别是与年龄相关的痴呆症的发生和发展有关。例如，最近的流行病学研究表明，肥胖的增加，特别是内脏肥胖，会增加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，啮齿动物饮食诱导的肥胖会引发多种神经紊乱，包括认知障碍和氧化应激标志物的增加。所有这些数据都表明HFD和内脏脂肪在Abeta相关痴呆的潜在重要临床调节剂中的重要作用。然而，目前膳食脂肪和肥胖调节大脑中Abeta发病机制的程度和机制尚不清楚。这一提议将验证饮食诱导的肥胖促进了Abeta病理改变的假设，以及相应的Abeta发病机制下游成分的增加，这部分依赖于内脏脂肪的增加。其次，本研究将验证内脏脂肪水平升高足以促进Abeta病理的假设，以及Abeta发病机制的下游成分。因此，该提案旨在解决（首次）内脏脂肪增加是否对HFD/肥胖诱导的脑效应是必要的关键问题，以及解决内脏脂肪增加是否足以增加脑发病机制。实验的重点将是Abeta病理的调节，以及Abeta病理的后果，使用脑淀粉样血管病（CAA）的小鼠模型。之所以选择CAA进行这些研究，是因为它既是血管性痴呆的病理底物，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下列每一个问题提供第一批定量措施。增加内脏脂肪是饮食性肥胖促进β病理的必要条件吗？内脏脂肪增加是否足以引起β病理改变？这些内脏脂肪对β病理的影响如何与脑损伤的特定行为和分子指标相关？

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?