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

项目总结/摘要 我们的假设是，营养过剩加上受损的膳食氨基酸周转可能发挥作用， 阿尔茨海默病（AD）发病机制。目标是通过营养来管理淀粉样蛋白和缠结体内平衡， 预防和治疗AD限制蛋白质、亮氨酸、蛋氨酸、支链氨基酸（BCAA）的摄入， 不限制卡路里摄入的啮齿类动物的寿命。Met或BCAA降解的失败是由遗传引起的 疾病--同型胱氨酸尿症和枫糖浆尿病--如果不治疗是致命的， 迟钝治疗包括限制Met或BCAA或Leu。因此，我们的假设是MR和BCAA- R可以通过限制代谢负荷和表观遗传变化来帮助管理和预防AD。主 本研究的目的是通过限制Met水平治疗AD小鼠模型中的淀粉样变性和tau蛋白病， 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 和其他营养素，代谢负荷的减少会导致空腹状态和淀粉样β（Aβ）蛋白的减少 前体（APP）水平，由于其快速周转（20分钟半衰期）。 这些研究将使用行为作为终点来衡量小鼠的整体健康状况。虽然行为是 这是一种复杂的变化，可能与变性和病理学没有线性关系，它提供了一个去/不去 改善心理健康的决定。 我们将使用对照组和限制组小鼠的组织来跟踪AD样神经病理学和神经元病理学。 完整性，以检验干预措施可以预防AD和相关痴呆症的假设。关于AD的大多数研究 主要研究Aβ和老年斑本研究的一个显著特点是，我们将确定 DR对Aβ、微管相关蛋白Tau（MAPT）和两种病变的组合的影响。 最后，最近已经认识到，微生物的数量与人类细胞相媲美，特别是在 消化道此外，研究表明，肠道微生物群可以影响营养，反之亦然， 积极和消极的方式，并影响免疫，代谢和神经功能。因此， 了解肠道微生物群组成，饮食调整和疾病结果之间的关系 了解肠道微生物对AD相关神经病理的饮食干预作用。我们将 因此检查所有治疗中的肠道微生物组。 由于APP增加1.5倍可诱导FAD，其表达随时间的小幅减少应 预防或延缓AD。饮食限制和锻炼可以提供有用的范例， 用于预防AD。

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.