Dietary Modification Of Brain Aging And Alzheimer's Disease

大脑衰老和阿尔茨海默病的饮食调整

基本信息

批准号：
9770106
负责人：
Mark Mattson
金额：
$ 24.69万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9770106
关键词：
Adenosine Monophosphate Adverse effects Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amygdaloid structure Animal Model Animals Anxiety Attenuated Autonomic nervous system Autopsy Bacterial Infections Bioenergetics Brain Brain Diseases Brain Injuries Brain Stem Brain-Derived Neurotrophic Factor CD14 Antigen Carbohydrates Cardiovascular system Cells Cellular Stress Response Cerebral cortex Characteristics Chemicals Coffee Cognition Cognitive deficits Congenital neurologic anomalies Corpus striatum structure Deposition Diet Diet Modification Dietary Component Dietary Factors Disease Drug Metabolic Detoxication Eating Elderly Energy Intake Energy Metabolism Energy-Generating Resources Enzymes Esters Evolution Exercise Exertion Exhibits Exposure to FGF2 gene FRAP1 gene Fasting Frequencies Functional disorder Health Health Benefit Heart Heart Rate Heat-Shock Proteins 70 Hippocampus (Brain)Human Huntington Disease Impairment Individual Inflammasome Inflammation Inflammatory Injury Insecta Insulin-Like Growth Factor I Interferons Interleukin-1 Interleukin-6 Intervention Trial Ischemic Stroke Ketone Bodies Ketones Learning Memory Messenger RNA Modeling Modernization Molecular Molecular Chaperones Motor Activity Mus NOS2A gene Nerve Degeneration Neurodegenerative Disorders Neuronal Plasticity Neurons Neurosecretory Systems Overweight Parkinson Disease Pathogenesis Pathology Pathway interactions Patients Performance Physiological Physiology Phytochemical Plants Poison Potential Energy Prevention Process Protein Kinase Proteins RANTES Rattus Regulation Reporting Research Resistance Rest Sepsis Serum Signal Pathway Sirtuins Spices Stress Stroke Substantia nigra structure TLR4 gene TNF gene Taste Perception Tea Testing Therapeutic Toxin abeta deposition aging brain antioxidant enzyme base behavior test biological adaptation to stress brain cell brain health cognitive function cognitive performance cytokine dietary manipulation dopaminergic neuron epidemiology study fruits and vegetables functional disability functional outcomes glucose-regulated proteins heme oxygenase-1 human subject hyperphosphorylated tau improved men&apos s group middle age mortality motor symptom mouse model mutant nervous system disorder neurochemistry neurotrophic factor novel post stroke prevent programs resilience response stroke model synuclein ward

项目摘要

Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of -synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals. In another study we found that mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle-aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain-derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase-1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice. We further found that intermittent fasting suppresses activation of the so-called 'inflammasome' in brain cells, which was associated with improved functional outcome in the mouse stroke model. We conclude that dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Abeta; deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the hippocampus and amygdala. These findings demonstrate a therapeutic benefit of a diet containing a ketone ester in a mouse model of Alzheimer's disease. The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Based on our own research and evolutionary considerations, we developed a novel hypothesis to explain the beneficial effects of diets rich in fruits and vegetables on health, including brain health. Plants do not have the option of fleeing predators. As a consequence, they have developed an elaborate set of chemical defenses to ward off insects and other creatures that want to make them into a meal. Toxins that plants use against predators are consumed by us at low levels in fruits and vegetables. Exposure to these chemicals causes a mild stress reaction that lends resilience to cells in our bodies. Adaptation to these stresses, a process called hormesis, accounts for a number of health benefits, including protection against brain disorders, that we receive from eating vegetables and fruits. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. We have elucidated some of the signaling pathways relevant to cellular energy metabolism that are modulated by 'neurohormetic phytochemicals' (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders. We fpimd that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-B activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1, IL-1 and TNF- levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1, IFN-, RANTES, TNF- and IL-6 levels. Taken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection.

帕金森氏病（PD）患者经常通过自主神经系统（ANS）表现出可能在运动症状之前的心率调节受损。尸检研究的结果表明，脑干病理学，包括 - 突触核蛋白的积累，先于PD中对多巴胺能神经元的损害。但是，尚不清楚导致脑干自主神经元早期功能障碍的分子和细胞机制。在这里，我们报告说，表达突变体突触核蛋白的小鼠对家族性PD表现出对心脏的异常自主控制，其特征是静息心率升高和心血管胁迫障碍，与副副交感神经活性降低以及脑干中突触塞糖蛋白的积累有关。这些ANS异常发生在疾病过程的早期。高能量饮食会加剧突触核素对心率控制的不利影响，并通过间歇性限制来改善。我们的发现建立了对PD中心血管系统的脑干控制早期失调的小鼠模型，并进一步提出了能量限制的潜力，以减轻ANS功能障碍，尤其是在超重的个体中。在另一项研究中，我们发现，局灶性缺血性中风的死亡率随着年龄的增长而增加，并通过间歇性禁食（如果）饮食降低。在年轻小鼠和老鼠中，IF减少了脑损伤和功能障碍。神经营养因子（脑衍生的神经营养因子和碱性成纤维细胞生长因子），蛋白伴侣（热休克蛋白70和葡萄糖调节蛋白78）的基础和后雷克斯水平和抗氧化剂血红素酶-1的炎症，而炎症酶的水平降低，降低与年轻小鼠相比，老鼠的大脑皮层和纹状体中的细胞因子增加。如果在年轻小鼠中协同增加了保护蛋白水平和炎症细胞因子的降低，但在老鼠中却没有。我们进一步发现，间歇性禁食抑制了脑细胞中所谓的“炎症体”的激活，这与小鼠冲程模型中的功能结果改善有关。我们得出的结论是，饮食能量摄入差异调节神经营养和炎症途径以保护神经元免受缺血性损伤，并且这些在衰老过程中受到损害的有益作用，从而导致脑损伤增加和功能较差。 3xtgad小鼠模型用于检验以下假设：基于酮酯的饮食可以改善AD发病机理。从预症状的年龄开始，将2组雄性3xtgad小鼠喂食，其中含有酮体的生理对映体前体（KET）或等含量碳水化合物饮食。饮食开始后4个月和7个月进行的行为测试结果表明，在2种不同的测试中，喂养小鼠的焦虑症明显较小。 3xtgad小鼠在KET饮食中也表现出显着的，尽管相对微妙，但在学习和记忆测试方面的表现有所改善。免疫组织化学分析表明，喂养的小鼠表现出Abeta的降低。在海马的下部，CA1和CA3区域中的沉积，以及杏仁核。喂养的小鼠在海马和杏仁核中表现出降低的高磷酸化tau沉积水平。这些发现证明了在阿尔茨海默氏病小鼠模型中含有酮酯的饮食的治疗益处。越来越多地赞赏饮食因素对大脑健康和疾病脆弱性的影响。流行病学研究的结果以及动物模型中的干预试验表明，富含植物化学物质的饮食可以增强神经可塑性和对神经变性的抗性。在这里，我们描述了动植物在共同进化过程中的相互作用以及由此产生的相互适应的如何塑造了植物化学物质的显着特征及其对整个动物细胞生理学的影响，尤其是神经元。根据我们自己的研究和进化考虑，我们开发了一种新颖的假设，以解释富含水果和蔬菜对健康（包括脑健康）的饮食的有益影响。植物没有逃避掠食者的选择。结果，他们开发了一套精心设计的化学防御措施，以抵御想要使它们成饭的昆虫和其他生物。植物对捕食者使用的毒素在水果和蔬菜中被低水平消耗。暴露于这些化学物质会引起轻度的压力反应，使我们体内细胞具有韧性。适应这些压力，即一种称为刺激性的过程，占了许多健康益处，包括保护脑部疾病，我们可以从吃蔬菜和水果中获得。赋予能够生产有害苦味化学物质的植物，以及能够耐受植物化学物质并消耗植物作为能源的动物。现代水果，蔬菜香料，茶和咖啡中存在的各种各样的植物化学物质可能部分是由于获取了动物中的自适应细胞应激反应和解毒酶，从而使它们能够消耗含有潜在有毒化学物质的植物。有趣的是，保护神经元免受有害植物化学物质的某些适应性压力反应机制也被饮食能量限制和剧烈的身体劳累激活，这两种环境挑战影响了大脑的进化。我们已经阐明了与细胞能代谢相关的一些信号通路，这些信号通路是由“神经化植物化学物质”调节的（植物产生的潜在毒性化学物质在中等量时对动物具有有益作用的毒性化学物质）。我们突出显示了与细胞生物能相关的西尔图蛋白，腺苷一磷酸激活蛋白激酶（AMPK），雷帕霉素（MTOR）的哺乳动物靶标（MTOR）和胰岛素样生长因子1（IGF-1）途径。饮食中的神经化植物化学物质包括在整个大脑健康计划中，其中还包括运动和能量限制，可能会在预防和治疗一系列神经系统疾病中发现应用。我们会说，如果通过涉及NF-B激活的机制来缓解败血症大鼠模型中的认知缺陷，抑制促炎细胞因子的表达以及对神经营养支持的增强。用LPS治疗大鼠会导致Barnes迷宫和抑制性回避测试的认知性能缺陷，而不会改变运动活性，而运动型在IF饮食上已维持的大鼠中得到了改善。如果还导致编码LPS受体TLR4和海马中诱导型一氧化氮合酶（INOS）的mRNA水平降低。此外，如果阻止了LPS诱导的IL-1，IL-1和TNF水平的升高，并防止了LPS诱导的海马中BDNF水平的降低。如果还显着减弱了LPS诱导的血清IL-1，IFN-，RANTES，TNF-和IL-6水平的升高。综上所述，我们的结果表明，如果诱导大脑和周围的适应性反应，可以抑制炎症并保留全身细菌感染模型中的认知功能。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hold the salt: vasopressor role for BDNF.

持盐：对于BDNF有升血管作用。

DOI：
10.1016/j.cmet.2015.03.015
发表时间：
2015
期刊：
Cell metabolism
影响因子：
29
作者：
Marosi,Krisztina;Mattson,MarkP
通讯作者：
Mattson,MarkP

Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons.

声波刺猬通路激活增加了海马神经元的线粒体丰度和活性。

DOI：
10.1091/mbc.e16-07-0553
发表时间：
2017
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Yao,PamelaJ;Manor,Uri;Petralia,RonaldS;Brose,RebeccaD;Wu,RyanTY;Ott,Carolyn;Wang,Ya-Xian;Charnoff,Ari;Lippincott-Schwartz,Jennifer;Mattson,MarkP
通讯作者：
Mattson,MarkP

Sphingolipid metabolism regulates development and lifespan in Caenorhabditis elegans.

DOI：
10.1016/j.mad.2014.11.002
发表时间：
2014-12-15
期刊：
MECHANISMS OF AGEING AND DEVELOPMENT
影响因子：
5.3
作者：
Cutler, Roy G.;Thompson, Kenneth W.;Camandola, Simonetta;Mack, Kendra T.;Mattson, Mark P.
通讯作者：
Mattson, Mark P.

Intermittent metabolic switching, neuroplasticity and brain health.