Dietary Modulation of Neuroinflammation in Age-Related Memory Disorders

饮食调节与年龄相关的记忆障碍中的神经炎症

• 批准号: 9975668
• 负责人: Richard P SLOAN
• 金额: $ 76.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975668
• 关键词: Active Biological Transport; Age; Age-Related Memory Disorders; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Binding; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood Pressure; Brain; Brain region; Cells; Clinical; Clinical Research; Clinical Trials; Cocoa Powder; Cognitive aging; Consumption; Data; Dementia; Development; Diet; Dietary Intervention; Dietary intake; Diffusion; Elderly; Endothelial Cells; Endothelium; Endotoxemia; Epidemic; Equipment; Family; Flavanol; Food; Functional Magnetic Resonance Imaging; Functional disorder; Goals; HMGB1 gene; Health; Healthcare Systems; Hippocampus (Brain); Human; Immune; Impaired cognition; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune System; Intake; Intervention; Investigation; Learning; Link; Measurable; Measures; Mediating; Mediation; Mediator of activation protein; Memory; Memory impairment; Methodology; Microglia; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Operative Surgical Procedures; Oral; Oxidative Stress; Parkinson Disease; Participant; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Pilot Projects; Placebos; Plants; Plasma; Population; Production; Quality of life; Randomized Controlled Trials; Recording of previous events; Reporting; Research; Rodent; Rodent Model; Role; Sentinel; Serological; Serum; Signal Pathway; Signal Transduction; Structure; Synaptic plasticity; TLR4 gene; TNF gene; Testing; Trauma; Validation; Variant; Vasomotor; age group; age related; base; bean; brain cell; brain dysfunction; cerebral blood volume; cognitive function; cytokine; dentate gyrus; dietary supplements; epicatechin; functional status; glymphatic system; group intervention; human old age (65+); imaging approach; improved; improved functioning; inflammatory marker; insulin sensitivity; macrophage; neurogenesis; neuroinflammation; neuronal survival; neuropathology; nonhuman primate; nutritional supplementation; post intervention; prevent; primary outcome; programs; prospective; septic patients; stem cells; therapeutic target; vascular inflammation

Within 25 years, the US population aged 65 and over will double in size to 80 million bringing, with it an epidemic of aging-related cognitive decline, from normal cognitive aging to neurodegenerative disorders including Alzheimer’s Disease (AD). These conditions impair quality of life and functional status, impose an enormous burden on individuals, their families, the healthcare system, and require elucidation of mechanisms and development of new treatments to prevent or at least slow their progression. The use of plant-based food and drink for health purposes has a long and well-documented history. Cocoa beans contain the flavanol epicatechin, an anti-oxidant with beneficial effects on blood pressure, endothelium- dependent vasomotor function, platelet reactivity, insulin sensitivity, vascular inflammation, and circulating progenitor cells. Importantly, flavanols have neuroprotective effects, suppressing oxidative stress and inflammation and promoting neurogenesis, neuronal survival and synaptic plasticity, all of which are relevant to the pathophysiology of neurodegenerative disorders like AD, amyotrophic lateral sclerosis (ALS), and Parkinson’s Disease (PD). Evidence from humans, non-human primates, and rodents points to a role for the hippocampus and its subregions in aging-related neurodegenerative disorders including AD. We recently reported that dietary intake of cocoa flavanols increased hippocampal function, measured as fMRI cerebral blood volume (CBV) and a pilot mediation analysis showed that cocoa flavanols led to a decrease in the sentinel pro-inflammatory mediator HMGB1, an activator of the innate immune system. In turn, this decrease in HMGB1 was linked to improved hippocampal function. Recent evidence implicates HMGB1 in cognitive decline and impairment. HMGB1 binds to Toll-like receptor 4 (TLR4), triggering the production of pro-inflammatory cytokines including TNFa via NFkB-dependent pathways. In rodent models of endotoxemia and surgical trauma, HMGB1 mediated hippocampal-dependent memory impairment similar to that seen in septic patients, an effect eliminated by neutralizing HMGB1. These data mechanistically link HMGB1 to neurodegenerative impairment, suggesting its potential as a therapeutic target, consistent with evidence that amplified systemic inflammation is associated with a variety of age-related pathologies including Alzheimer’s Disease. They strongly support our major hypothesis that cocoa flavanols improve hippocampal function by their effects on neuroinflammation, specifically HMGB1, via a TLR4-NFkB-TNFa signaling pathway. We propose to test this model in a randomized controlled trial of 146 participants, age 50-69, receiving high or low daily cocoa flavanol for 12 weeks. Such a trial has potential for significant clinical impact.

在25年内，美国65岁及以上的人口将翻一番，达到8000万，随之而来的是 从正常认知老化到神经退行性疾病，与衰老相关的认知衰退的流行 包括阿尔茨海默病(AD)。这些情况损害了生活质量和功能状态，迫使 给个人、他们的家庭和医疗保健系统带来巨大负担，并需要阐明机制 以及开发新的治疗方法来防止或至少减缓它们的进展。 以植物为基础的食品和饮料用于健康目的已经有很长的历史，而且有充分的文件记录。可可 豆类含有黄烷醇、表儿茶素，这是一种抗氧化剂，对血压、血管内皮细胞有好处。 依赖性血管运动功能、血小板反应性、胰岛素敏感性、血管炎症和循环 祖细胞。重要的是，黄烷醇具有神经保护作用，抑制氧化应激和 炎症和促进神经发生、神经元存活和突触可塑性，所有这些都与 神经退行性疾病如AD、肌萎缩侧索硬化症(ALS)和 帕金森氏病(PD)。 来自人类、非人类灵长类动物和啮齿动物的证据表明，海马体及其 包括阿尔茨海默病在内的衰老相关神经退行性疾病的亚区。我们最近报道说，饮食 摄取可可黄烷醇可增加海马区功能，以功能磁共振脑血容量(CBV)和 一项初步的中介分析表明，可可黄烷醇导致前哨促炎作用的减少。 调节剂HMGB1，先天免疫系统的激活剂。反过来，HMGB1的这种下降与 改善了海马体功能。最近的证据表明，HMGB1与认知能力下降和功能障碍有关。 HMGB1与Toll样受体4(TLR4)结合，触发促炎细胞因子的产生，包括 TnFa通过NFkB依赖的途径。在内毒素血症和手术创伤的啮齿动物模型中，HMGB1 类似于脓毒症患者所见的介导的海马区依赖记忆障碍，一种效果 通过中和HMGB1消除。 这些数据机械地将HMGB1与神经退行性损伤联系起来，表明它作为一种 治疗目标，与放大的全身炎症与多种疾病相关的证据一致 与年龄相关的病理，包括阿尔茨海默病。他们强烈支持我们的主要假设，即可可 黄烷醇通过对神经炎症的影响，特别是HMGB1，通过一种 TLR4-NFkB-TNFa信号通路。我们建议在146人的随机对照试验中测试该模型 参与者，年龄在50-69岁之间，每天摄入或高或低的可可黄醇，为期12周。这样的试验有可能 对临床有重大影响。