Neuroprotective And Neurorestorative Signaling Mechanisms

神经保护和神经恢复信号机制

• 批准号: 8931506
• 负责人: Mark Mattson
• 金额: $ 48.59万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 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/8931506
• 关键词: 1-Phosphatidylinositol 3-Kinase; AS101; Adverse effects; Affect; Age; Aging-Related Process; Alzheimer' s Disease; Alzheimer' s disease model; Amygdaloid structure; Amyloid; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Anxiety; Attenuated; Autonomic nervous system; Autophagocytosis; Autophagosome; Autopsy; Behavioral; Biogenesis; Blood Pressure; Brain; Brain Stem; Brain region; Brain-Derived Neurotrophic Factor; Carbohydrates; Cardiovascular system; Cessation of life; Clinical Trials; Cognitive; Cognitive deficits; Complex; Congenital neurologic anomalies; Curcumin; Cyclic AMP-Responsive DNA-Binding Protein; Cytoplasmic Granules; Dendritic Spines; Deposition; Development; Diet; Dietary Phytochemical; Disease; Electron Microscopy; Embryonic Development; Energy Metabolism; Erinaceidae; Esters; Etiology; Exercise; Exhibits; Experimental Models; Fasting; Functional disorder; Gene Expression; Genes; Glucose; Glutamates; Glutaminase; Goals; Growth Factor; Heart; Heart Rate; Hippocampus (Brain); Hormones; Huntington Disease; Immune; Immune response; Immunoblot Analysis; Impaired cognition; Individual; Inflammatory; Ion Channel; Ketone Bodies; Ketones; Lead; Learning; Link; Maintenance; Mediating; Mediator of activation protein; Memory; Memory impairment; Metabolic stress; Microarray Analysis; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; Molecular Weight; Morphology; Motor; Multiple Sclerosis; Mus; N-Methyl-D-Aspartate Receptors; Neural tube; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic Dysfunctions; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Overweight; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Performance; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological; Physiology; Phytochemical; Potential Energy; Presynaptic Terminals; Process; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Stroke; Structure; Substantia nigra structure; Symptoms; Synapses; TNFRSF1B gene; Tellurium; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Up-Regulation; base; behavior test; biological adaptation to stress; cytokine; density; design; dietary restriction; dopaminergic neuron; excitotoxicity; feeding; human subject; hyperphosphorylated tau; immunocytochemistry; in vivo; men' s group; mouse model; mutant; nervous system disorder; neurorestoration; neurotrophic factor; normal aging; novel; overexpression; peptide A; receptor; research clinical testing; response; smoothened signaling pathway; synaptogenesis; synuclein

We have identified several growth factors and cytokines that can protect neurons against dysfunction and death in experimental models of Alzheimers disease, Parkinsons disease and stroke. These trophic factors activate signaling pathways that stimulate the expression of genes whose encoded proteins increase resistance of neurons to oxidative and metabolic stress. Neuroprotective Actions of BDNF. We have found that brain-derived neurotrophic factor (BDNF) is a key mediator of the neuroprotective effects of dietary restriction in animal models of Parkinsons and Huntingtons diseases. 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. The Sonic hedgehog (Shh) signaling pathway is well known in patterning of the neural tube during embryonic development, but its emerging role in differentiated neurons is less understood. Here we report that Shh enhances autophagy in cultured hippocampal neurons. Microarray analysis reveals the upregulation of multiple autophagy-related genes in neurons in response to Shh application. Through analysis of the autophagy-marker LC3 by immunoblot analysis and immunocytochemistry, we confirm activation of the autophagy pathway in Shh-exposed neurons. Using electron microscopy, we find autophagosomes and associated structures with a wide range of morphologies in synaptic terminals of Shh-exposed neurons. Moreover, we show that Shh-triggered autophagy depends on class III Phosphatidylinositol 3-kinase complexes (PtdIns3K). These results identify a link between Shh and autophagy pathways and, importantly, provide a lead for further understanding the physiology of Shh signaling activity in neurons. Alzheimer's disease (AD) involves progressive accumulation of amyloid β-peptide (Aβ) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. 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 Aβ 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 same regions of the hippocampus, amygdala, and cortex. Thus, a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model. The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses. A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se. We have recently found that the tellurium compound AS101 has a therapeutic benefit in a mouse model of multiple sclerosis. We have also found that BDNF stimulates mitochondrial biogenesis and promotes the formation and maintenance of synapses in the hippocampus of mice. In addition, BDNF signaling in the brainstem enhances parasympathetic regulation of the heart which may mediate the beneficial effects of exercise and intermittent fasting on heart rate and blood pressure.

我们已经确定了几种生长因子和细胞因子，可以保护神经元在阿尔茨海默氏病，帕金森氏病和中风的实验模型中保护神经元免受功能障碍和死亡。这些营养因子激活了信号通路，刺激其编码蛋白的基因表达增加了神经元对氧化和代谢应激的抗性。 BDNF的神经保护作用。我们发现，脑衍生的神经营养因子（BDNF）是帕金森氏症和亨廷顿疾病动物模型中饮食限制的神经保护作用的关键介体。 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，表达突变形式的 - 突触核蛋白的小鼠会导致家族性PD表现出对心脏的异常自主性控制，其特征是静息心率升高和心血管应激障碍的受损，与副交感神经活性降低以及脑部中 - 核蛋白的积累有关。这些ANS异常发生在疾病过程的早期。高能量饮食会加剧 - 突触核蛋白对控制心率的不利影响，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。 声音刺猬（SHH）信号传导途径在胚胎发育过程中众所周知，但其在分化神经元中的新兴作用尚不清楚。在这里，我们报告说，SHH在培养的海马神经元中增强了自噬。微阵列分析揭示了响应于SHH应用的神经元中多个自噬相关基因的上调。通过免疫印迹分析和免疫细胞化学对自噬标记LC3的分析，我们确认了暴露于SHH暴露的神经元中自噬途径的激活。使用电子显微镜，我们在暴露于SHH暴露的神经元的突触末端发现自噬小体和相关结构。此外，我们表明，SHH触发的自噬取决于III类磷脂酰肌醇3-激酶复合物（PTDINS3K）。这些结果确定了SHH与自噬途径之间的联系，重要的是，为进一步理解神经元中SHH信号活性的生理提供了铅。 阿尔茨海默氏病（AD）涉及淀粉样β-肽（Aβ）和神经原纤维病理的逐步积累，以及在记忆至关重要的大脑区域中葡萄糖低代谢。 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，喂养小鼠的小鼠在海马的亚蛋白，CA1和CA3区域以及杏仁核中表现出降低的Aβ沉积。喂养的小鼠在海马，杏仁核和皮质的同一地区表现出降低的高磷酸化tau沉积水平。因此，新型的酮酯可以在小鼠AD模型中改善蛋白质病和行为缺陷。 突触的形成，维护和重组对于大脑发育以及神经元电路对环境挑战的反应至关重要。在这里，我们描述了过氧化物酶体增殖物激活的受体γ共激活剂1α，即线粒体生物发生的主要调节剂，在海马神经元中树突状棘的形成和维持中。在培养的海马神经元中，增生剂激活的受体γ共激活剂1α过表达增加了树突状刺并增强了突触的分子分化，而敲除增殖器激活的受体γ共驱动器γ共驱动器1α抑制了抑制微分发生和突发发生。增殖物激活的受体γ共激活剂1α敲低还降低了体内海马齿状颗粒神经元中树突状棘的密度。我们进一步表明，脑源性神经营养因子通过激活细胞外信号调节激酶和环状AMP反应元件结合蛋白来刺激增生剂激活的受体γ共激活剂1α依赖性线粒体生物发生。增生剂激活的受体γ共激活剂1α敲低抑制脑衍生的神经营养因子诱导的树突状脊柱形成，而不会影响脑源性神经营养因子受体受体受体激酶的表达和激活。 -Activator-1α和线粒体生物发生在海马树突状棘和突触的形成和维持中具有重要作用。 认知能力的下降是正常衰老过程的典型特征，也是阿尔茨海默氏症，帕金森氏症和亨廷顿疾病等神经退行性疾病的典型特征。尽管它们的病因不同，但所有这些疾病都涉及先天免疫途径和相关炎症细胞因子的局部激活。但是，神经退行性疾病中抗炎药的临床试验令人失望，因此有必要更好地了解炎症过程在神经功能障碍中的复杂作用。饮食中的植物化学姜黄素可以发挥抗炎，抗氧化剂和神经保护作用。在这里，我们提供的证据表明姜黄素通过需要功能性肿瘤坏死因子α受体2（TNFR2）信号传导的机制来缓解与先天免疫反应相关的认知缺陷。在体内，姜黄素抵消海马依赖性空间记忆缺陷的能力，刺激诸如BDNF上调的神经保护机制，降低谷氨酰胺酶水平，并调节缺乏功能性TNFRS的小鼠缺乏N-甲基-D-天冬氨酸受体水平。姜黄素治疗通过需要TNFR2激活的机制保护培养的神经元免受谷氨酸诱导的兴奋性。我们的结果表明，针对旨在选择性增强TNFR2信号传导的认知下降的治疗方法可能比使用抗炎药本身更有益。 我们最近发现，牙槽化合物AS101在多发性硬化症的小鼠模型中具有治疗益处。 我们还发现，BDNF刺激线粒体生物发生，并促进小鼠海马中突触的形成和维护。 此外，脑干中的BDNF信号传导增强了心脏的副交感神经调节，这可能介导运动和间歇性禁食对心率和血压的有益作用。