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

饮食限制和肠道微生物群的相关变化可预防阿尔茨海默病

基本信息

批准号：
9905467
负责人：
KUMAR SAMBAMURTI
金额：
$ 18.69万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905467
关键词：
APP-PS1 Affect Age-Months Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amino Acids Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloidosis Anti-Cholinergics Behavior Behavioral Benzodiazepines Biological Markers Branched-Chain Amino Acids Breeding Caloric Restriction Calories Cells Characteristics Cholesterol Complementary DNA Complex Coupled Dementia Deposition Diabetes Mellitus Diet Diet Modification Dietary Intervention Disease Disease Outcome Distal Epigenetic Process Essential Amino Acids Evaluation Exercise Failure Fasting Future Gastrointestinal tract structure Gene Expression Genes Genomics Genotype Goals Half-Life Health Healthcare Systems Hereditary Disease Homeostasis Homocysteine Homocystinuria Human Hypertension Immune Impairment Insulin Resistance Intervention Lesion Link Lipids Longevity MAPT gene Maple Syrup Urine Disease Measures Mental Health Mental Retardation Metabolic Methods Microbe Minor Modification Mus Mutation Nervous System Physiology Neurofibrillary Tangles Neurons Nutrient Nutritional Obesity Outcome Measure Overnutrition PTK2B gene Pathogenesis Pathology Pattern Pharmaceutical Preparations Play Presenile Alzheimer Dementia Prevention Prions Protein Precursors Proteins Quality of life Rattus Retirement Risk Factors Rodent Role Senile Plaques Shapes Signal Pathway Structure Symptoms Tauopathies Testing Time Tissues Transgenes Transgenic Organisms age related age related neurodegeneration apolipoprotein E-4 base civil society dietary requirement dietary restriction experimental study familial Alzheimer disease gut microbes gut microbiome gut microbiota improved insulin sensitivity leucylmethionine microbiota mouse model mutant neuropathology normal aging nutrition oxidative damage presenilin-1 presenilin-2 preservation prevent promoter rRNA Genes tool transcriptome treatment comparison

项目摘要

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.

项目摘要/摘要我们的假设是，营养不良以及受损的饮食氨基酸周转率可能在阿尔茨海默氏病（AD）发病机理。目标是通过营养来管理淀粉样蛋白和缠结的稳态预防和治疗广告。蛋白质，LEU，MET，分支链氨基酸（BCAA）的限制可以改善无卡路里限制的啮齿动物的寿命。 MET或BCAA降解的失败是由继承引起的疾病 - 同囊尿和枫糖浆尿液疾病 - 未经治疗并引起精神迟钝。治疗包括限制MET，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广告。主要这项研究的目的是通过限制MET水平和将治疗方法与其他饮食限制（DR）方法进行比较。我们建议通过限制和其他营养素，减少的代谢负荷将导致禁食条件并降低淀粉样β（Aβ）蛋白前体（APP）水平由于其快速营业额（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。虽然行为是一个复杂的变化可能与发育和病理学无线性相关，它提供了GO/NO GO 改善心理健康的决定。我们将使用对照和受限小鼠的组织遵循广告状神经病理学和神经元综合性测试干预措施可以防止AD和相关痴呆症的假设。大多数广告研究专注于Aβ和老年斑块。当前研究的一个显着特征是我们将确定效果 Aβ上的DR，微管相关蛋白TAU（MAPT）和文献中两个病变的组合。最后，最近已经认识到，微生物的数量是丝带人类细胞的数量消化道。此外，研究表明，肠道菌群会影响营养，反之亦然，在积极和负面的方式以及影响免疫学，代谢和神经功能。因此，这很重要了解肠道菌群组成，饮食修饰和疾病结局之间的关联实现肠道微生物对AD相关神经病理学饮食干预的贡献。我们将因此，检查所有治疗方法中的肠道微生物组。由于应用程序增加了1.5 x可以诱导时尚，因此随着时间的流逝，其表达的少量减少应预防或延迟广告。饮食限制和运动可能会提供有用的范例实施用于预防AD。