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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.

帕金森病 (PD) 患者经常表现出自主神经系统 (ANS) 对心率的调节受损，在许多情况下，这可能先于运动症状出现。尸检研究结果表明，脑干病理学（包括 β-突触核蛋白的积累）先于 PD 黑质中的多巴胺能神经元受损。然而，导致脑干自主神经元早期功能障碍的分子和细胞机制尚不清楚。在此，我们报道，表达导致家族性 PD 的突触核蛋白突变体的小鼠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应激反应受损，与副交感神经活动减少和脑干中突触核蛋白积累有关。这些 ANS 异常发生在疾病过程的早期。突触核蛋白对心率控制的不利影响因高能量饮食而加剧，并因间歇性能量限制而改善。我们的研究结果建立了 PD 中心血管系统脑干控制早期失调的小鼠模型，并进一步表明能量限制有可能减轻 ANS 功能障碍，特别是在超重个体中。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，并且通过间歇性禁食（IF）饮食而降低。 IF 可以减少年轻和中年小鼠的脑损伤和功能障碍，但不能减少老年小鼠的脑损伤和功能障碍。与对照组相比，老年小鼠大脑皮层和纹状体的神经营养因子（脑源性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）和抗氧化酶血红素氧合酶-1的基础和中风后水平降低，而炎症细胞因子水平升高。年轻的老鼠。 IF 可以协调地增加年轻小鼠的保护蛋白水平并减少炎症细胞因子，但在年老小鼠中则不然。我们进一步发现，间歇性禁食会抑制脑细胞中所谓“炎症小体”的激活，这与小鼠中风模型中功能结果的改善有关。我们得出的结论是，膳食能量摄入会差异性地调节神经营养和炎症途径，以保护神经元免受缺血性损伤，而间歇性间歇性的这些有益作用在衰老过程中会受到损害，导致脑损伤增加和功能结果较差。 3xTgAD 小鼠模型用于检验基于酮酯的饮食可以改善 AD 发病机制的假设。从症状出现前的年龄开始，给两组雄性 3xTgAD 小鼠喂食含有酮体生理对映体前体 (KET) 的饮食或等热量碳水化合物饮食。开始饮食后 4 个月和 7 个月进行的行为测试结果显示，KET 喂养的小鼠在 2 项不同的测试中表现出明显较少的焦虑。采用 KET 饮食的 3xTgAD 小鼠在学习和记忆测试中也表现出显着（尽管相对微妙）的表现改善。免疫组织化学分析显示，KET 喂养的小鼠表现出 Abeta 降低；沉积于下托、海马 CA1 和 CA3 区以及杏仁核。 KET 喂养的小鼠海马和杏仁核中过度磷酸化的 tau 蛋白沉积水平降低。这些发现证明了含有酮酯的饮食对阿尔茨海默病小鼠模型具有治疗作用。饮食因素对大脑健康和疾病易感性的影响越来越受到重视。流行病学研究和动物模型干预试验的结果表明，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抵抗力。在这里，我们描述了植物和动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如何塑造了植物化学物质的显着特征及其对动物细胞，特别是神经元生理学的影响。基于我们自己的研究和进化方面的考虑，我们提出了一个新的假设来解释富含水果和蔬菜的饮食对健康（包括大脑健康）的有益影响。植物没有逃避掠食者的选择。因此，它们开发出了一套复杂的化学防御系统来抵御昆虫和其他想要将它们变成食物的生物。植物用来对抗捕食者的毒素被我们消耗在水果和蔬菜中，含量很低。接触这些化学物质会引起轻微的应激反应，从而增强我们体内细胞的弹性。对这些压力的适应过程称为毒物兴奋效应，它可以带来许多健康益处，包括预防大脑疾病，这是我们通过吃蔬菜和水果获得的。能够产生有毒苦味化学物质的植物和能够耐受植物化学物质并将植物作为能量来源的动物被赋予了生存优势。现代水果、蔬菜香料、茶和咖啡中存在的极其多样化的植物化学物质可能部分源于动物获得适应性细胞应激反应和解毒酶，使它们能够食用含有潜在有毒化学物质的植物。有趣的是，一些保护神经元免受有害植物化学物质侵害的相同适应性应激反应机制也被饮食能量限制和剧烈体力消耗所激活，这两种环境挑战塑造了大脑的进化。我们已经阐明了一些与细胞能量代谢相关的信号传导途径，这些信号传导途径受“神经激素植物化学物质”（植物产生的潜在有毒化学物质，适量食用时对动物产生有益影响）调节。我们重点介绍细胞生物能学相关的 Sirtuin、腺苷单磷酸激活蛋白激酶 (AMPK)、哺乳动物雷帕霉素靶标 (mTOR) 和胰岛素样生长因子 1 (IGF-1) 通路。将膳食神经激素植物化学物质纳入大脑健康整体计划（还包括运动和能量限制）可能会应用于预防和治疗一系列神经系统疾病。我们发现，IF 通过涉及 NF-B 激活、抑制促炎细胞因子表达和增强神经营养支持的机制改善脓毒症大鼠模型中的认知缺陷。用LPS治疗大鼠会导致巴恩斯迷宫和抑制性回避测试中的认知表现缺陷，但不改变运动活动，而在维持IF饮食的大鼠中，这种情况得到改善。 IF 还导致海马中编码 LPS 受体 TLR4 和诱导型一氧化氮合酶 (iNOS) 的 mRNA 水平降低。此外，IF 可防止 LPS 诱导的海马 IL-1、IL-1 和 TNF-α 水平升高，并防止 LPS 诱导的 BDNF 水平降低。 IF 还显着减弱 LPS 诱导的血清 IL-1、IFN-、RANTES、TNF- 和 IL-6 水平升高。综上所述，我们的结果表明，IF 会诱导大脑和外周的适应性反应，从而在全身细菌感染的动物模型中抑制炎症并保持认知功能。

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.

Sonic Hedgehog Signaling and Hippocampal Neuroplasticity.