Dietary restriction and associated changes in gut microbiota to prevent Alzheimer disease

项目摘要/摘要 我们的假设是，营养过剩加上饮食中氨基酸代谢受损，可能在 阿尔茨海默病(AD)的发病机制。目标是通过营养来管理淀粉样蛋白和缠绕的动态平衡 防治阿尔茨海默病。限制蛋白质、亮氨酸、蛋氨酸、支链氨基酸(BCAA) 不限制卡路里的啮齿动物的寿命。蛋氨酸或支链氨基酸降解失败是由遗传引起的 疾病--同型半胱氨酸尿症和枫树糖浆尿症--如果不治疗就会致命，并会导致精神疾病 智力迟缓。治疗方法包括限制Met或BCAA或Leu。因此，我们的假设是先生和BCAA- R可以通过限制代谢负荷和表观遗传学变化来帮助管理和预防AD。初级阶段 本研究的目的是通过限制蛋氨酸水平和肌萎缩侧索硬化症的水平来治疗阿尔茨海默病小鼠模型中的淀粉样变性和肌萎缩症。 将这些治疗方法与其他饮食限制(DR)方法进行比较。我们建议通过限制Met 和其他营养物质，代谢负荷的减少会导致空腹状态和淀粉样蛋白(Aβ，Aβ)的减少 前体(APP)水平由于其快速周转(20分钟半衰期)。 这些研究将以行为为终点来衡量小鼠的整体健康状况。尽管行为是 一种复杂的变化，可能与退变和病理不是线性相关的，它提供了一个通过/不通过的过程 改善心理健康的决定。 我们将使用对照组和受限小鼠的组织来跟踪AD样的神经病理和神经元 以检验干预可以预防阿尔茨海默病和相关痴呆的假设。大多数关于AD的研究 都专注于Aβ和老年斑。当前研究的一个显著特点是，我们将确定 在窝产仔中，DR on Aβ、微管相关蛋白Tau(MAPT)以及两者的组合。 最后，最近人们认识到，微生物的数量可以与人类细胞相媲美，特别是在 消化道。此外，研究表明，肠道微生物区系可以影响营养，反之亦然。 无论是积极的还是消极的，都会影响免疫、代谢和神经功能。因此，它是重要的 了解肠道微生物区系组成、饮食结构调整和疾病结局之间的关系 了解肠道微生物在饮食干预AD相关神经病理中的作用。我们会 因此，在所有的治疗中都要检查肠道微生物群。 由于APP的1.5倍增加会引发FAD，随着时间的推移，其表达的小幅减少应该 预防或延迟AD。饮食限制和锻炼可能会提供有用的范例，这些范例可能很容易 为预防AD而实施。

PROJECT SUMMARY/ABSTRACT Our hypothesis is that overnutrition coupled with impaired dietary amino acid turnover may play a role in Alzheimer disease (AD) pathogenesis. goals are to manage amyloid and tangle homeostasis by nutrition to prevent and treat AD. Restriction of protein, Leu, Met, branched-chain amino acids (BCAA) can improve longevity in rodents without calorie restriction. Failure of Met or BCAA degradation are caused by inherited diseases -- homocystinuria and maple syrup urine disease -- that are fatal when untreated and cause mental retardation. Treatments include restricting Met or BCAA or Leu. Therefore, our hypothesis is that MR and BCAA- R can help in managing and preventing AD by limiting metabolic load and epigenetic changes. The primary purpose of this study is to treat amyloidosis and tauopathy in an AD mouse model by restricting Met levels and to compare the treatments with other dietary restriction (DR) approaches. We propose that by restricting Met and other nutrients, the reduced metabolic load will lead to a fasting condition and reduce amyloid β (Aβ) protein precursor (APP) levels due to its rapid turnover (20 min half-life). The studies will use behavior as an endpoint to measure overall health of the mice. Although behavior is a complex change that may not linearly correlate with degeneration and pathology, it provides a go/no go decision for mental health improvement. We will use tissues from control and restricted mice to follow AD-like neuropathology and neuronal integrity to test the hypothesis that the interventions can prevent AD and related dementias. Most studies on AD have focused on Aβ and senile plaques. A salient feature of the current study is that we will determine the effects of DR on Aβ, Microtubule-associated protein Tau (MAPT) and a combination of both lesions in littermates. Finally, it has recently been recognized that the number of microbes rival human cells particularly in the alimentary canal. Moreover, studies have shown that the gut microbiota can affect nutrition, and vice versa, in both positive and negative ways and impact immune, metabolic and neurological functions. Hence, it is important to understand the associations between gut microbiota composition, dietary modification and disease outcome to realize the contribution of gut microbes to dietary intervention of AD associated neuropathology. We will therefore examine the gut microbiome in all the treatments. Since a 1.5 x increase in APP can induce FAD, the small reduction over time in its expression should prevent or delay AD. Dietary restriction and exercise may provide useful paradigms that may be readily implemented for prevention of AD.