Neuroprotective And Neurorestorative Signaling Mechanisms

神经保护和神经恢复信号机制

• 批准号: 8552362
• 负责人: Mark Mattson
• 金额: $ 53.65万
• 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/8552362
• 关键词: Adrenalectomy; Adverse effects; Alzheimer' s Disease; Animal Model; Antioxidants; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Autopsy; Behavior; Botanicals; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Caenorhabditis elegans; Cardiovascular system; Cell Nucleus; Cells; Cellular Stress Response; Cessation of life; Cognitive; Complement; Complement 1q; Congenital neurologic anomalies; Control Groups; Corticosterone; Diabetes Mellitus; Diet; Disease; Disease Progression; Dose; Electroconvulsive Therapy; Energy Metabolism; Enzymes; Exercise; Exhibits; Experimental Models; Exposure to; Fasting; Free Radicals; Functional disorder; Gene Expression; Goals; Growth Factor; Heart; Heart Rate; Hippocampus (Brain); Hormones; Human; Huntington Disease; Individual; Intravenous Immunoglobulins; Ion Channel; Ischemic Stroke; Kainic Acid; Lead; Learning; Link; Longevity; Mammalian Cell; Measures; Mediating; Mediator of activation protein; Memory impairment; Metabolic stress; Modeling; Molecular; Molecular Chaperones; Molecular Weight; Motor; Mus; Mutant Strains Mice; Naphthoquinones; Nematoda; Nerve Degeneration; Neurologic; Neuronal Dysfunction; Neurons; Neuropeptides; Neurotoxins; Operative Surgical Procedures; Overweight; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Patients; Peptides; Performance; Pesticides; Physiological; Phytochemical; Potential Energy; Process; Proteins; Rattus; Regimen; Regulation; Reporter; Reporting; Resistance; Rest; Screening procedure; Series; Signal Pathway; Signal Transduction; Staging; Stress; Stroke; Substantia nigra structure; Supplementation; Symptoms; Up-Regulation; Vitamin K 3; age effect; analog; anti aging; biological adaptation to stress; brain cell; cytokine; dietary restriction; dopaminergic neuron; exenatide; feeding; genetic analysis; glucagon-like peptide; human Huntingtin protein; human subject; in vivo; inhibitor/antagonist; mouse model; mutant; nervous system disorder; neuron loss; neuroprotection; neurorestoration; neurotrophic factor; new therapeutic target; novel; plumbagin; prevent; research clinical testing; research study; response; restraint stress; synuclein; thermal stress; transcription factor

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. We identified GLP-1 (glucagon-like peptide 1) as a neuroprotective neuropeptide with the potential to ameliorate neuronal dysfunction and degeneration in some neurodegenerative conditions. We have demonstrated the ability of exendin-4, a GLP-1 analog used to treat diabetes, to ameliorate neurological deficits in animal models of stroke, Huntington's disease, Parkinson's disease and Alzheimer's disease. We are currently performing a clincial trial of exendin-4 in patients who are in the early stages of Alzheimer's disease. We have identified several novel neuroprotective strategies in animal models including: intermittent electroconvulsive shock therapy slows disease progression and extends survival in Huntingtin mutant mice; Alternate day fasting protects the brain against ischemic stroke by a mechanism involving the upregulation of BDNF, protein chaperones and antioxidant enzymes in brain cells; treatment of mice with intravenous immunoglobulin or a specific peptide inhibitor of the complement protein C1q, is highly neuroprotective in stroke model. Experimental models of diabetes in rats and mice have demonstrated that reduction of corticosterone (CORT; a stress hormone) reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-AL KA group demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH-DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, BDNF, transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH-DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower-than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms. Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD. Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap'n'collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway. 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.

我们已经确定了几种生长因子和细胞因子，可以在阿尔茨海默病、帕金森病和中风的实验模型中保护神经元免受功能障碍和死亡。这些营养因子激活信号通路，刺激基因的表达，这些基因编码的蛋白质可增强神经元对氧化和代谢应激的抵抗力。 BDNF 的神经保护作用。我们发现，脑源性神经营养因子（BDNF）是帕金森病和亨廷顿病动物模型中饮食限制的神经保护作用的关键介质。 我们将 GLP-1（胰高血糖素样肽 1）确定为一种神经保护性神经肽，具有改善某些神经退行性疾病中神经元功能障碍和变性的潜力。 我们已经证明了 exendin-4（一种用于治疗糖尿病的 GLP-1 类似物）能够改善中风、亨廷顿病、帕金森病和阿尔茨海默病动物模型中的神经缺陷。 我们目前正在阿尔茨海默病早期患者中进行 exendin-4 的临床试验。 我们在动物模型中确定了几种新颖的神经保护策略，包括：间歇性电惊厥休克疗法可减缓亨廷顿突变小鼠的疾病进展并延长生存期； 隔日禁食通过上调脑细胞中 BDNF、蛋白伴侣和抗氧化酶的机制来保护大脑免受缺血性中风的影响；用静脉注射免疫球蛋白或补体蛋白 C1q 的特定肽抑制剂治疗小鼠，对中风模型具有高度的神经保护作用。 大鼠和小鼠糖尿病实验模型表明，减少皮质酮（CORT；一种应激激素）可以减少学习和记忆缺陷，并减轻神经元活力和可塑性的丧失。与 GC 水平升高的负相关相反，在饮食限制 (DR) 范式中 CORT 适度升高，这与许多健康的抗衰老作用（包括神经保护）相关。我们在大鼠中证明，在 DR 方案 (ADX-DR) 开始之前，通过肾上腺切除术 (ADX) 补充至相对较低的水平（比对照低 30%），然后中枢施用神经毒素红藻氨酸，以消除 CORT (KA)，显着减轻 14 单元 T 迷宫任务中的学习缺陷。 ADX-DR KA 组的表现与未接受 KA 且随意进食的对照组 (CON) 没有差异。相比之下，与 CON 组相比，假手术 DR (SHAM-DR KA) 组、SHAM-AL KA 组和 ADX-AL KA 组在此任务中表现出较差的学习行为。体视学分析显示，通过海马 CA2/CA3 区域的细胞损失来测量，SH-DR KA 和 ADX-DR KA 组中 DR 诱导的神经保护作用相当，而在 SH-AL 和 ADX-AL 中观察到大量细胞损失老鼠。在相似的饮食和手术治疗条件下进行了一组单独的实验，但没有给予 KA，以检查神经营养活性标记物、BDNF、转录因子 (pCREB) 和伴侣蛋白 (HSP-70)。在这些条件下，我们注意到与其他组相比，ADX DR 大鼠的 BDNF 和 pCREB ​​均升高；而 HSP-70 在 ADX-DR 和 SH-DR 组中同样升高，并且高于在 SH-AL 和 ADX-AL 组中观察到的水平。这些结果支持 DR 保护海马神经元免受 KA 诱导的细胞损伤的发现。然而，在 ADX 导致的 CORT 水平低于对照水平并通过外源性 CORT 补充剂维持的大鼠中，这种神经保护作用进一步增强。我们的结果表明，DR 诱导的 GC 生理性升高可能会对 DR 诱导的有益作用产生负面的功能后果。然而，这些负面影响可以通过其他 DR 产生的细胞和分子保护机制来补偿。 亨廷顿病 (HD) 与严重的自主神经功能障碍有关，包括心血管控制失调，通常先于认知或运动症状出现。 HD 患者和 HD 小鼠模型大脑中的脑源性神经营养因子 (BDNF) 水平降低，恢复 BDNF 水平可以防止 HD 小鼠的神经元损失并延长生存期。我们推断，HD 中心率的变化可能与脑干心血管控制核中 BDNF 信号的改变有关。在这里，我们发现 HD (N171-82Q) 小鼠在症状前和疾病早期阶段的心率升高，并且心率对约束应激的反应减弱。 HD 小鼠和人类 HD 患者中含有心血管核的脑干区域的 BDNF 水平显着降低。 BDNF 的中央管理使心率恢复到控制水平。我们的研究结果建立了 HD 小鼠脑干心血管核中 BDNF 表达减少与心率异常之间的联系，并提出了纠正 HD 心血管功能障碍的新治疗靶点。 当低水平的压力引发适应性有益反应时，就会发生毒物兴奋效应，从而防止随后暴露于严重压力。最近的研究结果表明，轻度氧化和热应激可以通过毒物兴奋机制延长寿命。在这里，我们表明，植物农药白花丹素虽然在高剂量时对秀丽隐杆线虫有毒，但在低剂量时可延长寿命。由于白花丹素是一种可以在体内产生自由基的萘醌，我们研究了它是否通过激活适应性细胞应激反应途径来延长寿命。线虫帽领 (CNC) 转录因子 SKN-1 介导对氧化应激的保护性反应。遗传分析表明，skn-1 活性是低剂量白花丹素延长线虫寿命所必需的。对一系列白花丹素类似物的进一步筛选确定了另外三种萘醌，它们可以诱导秀丽隐杆线虫中的 SKN-1 靶点。与白花丹素相比，萘醌在更大的剂量范围内表现出 skn-1 依赖性寿命延长，而其他萘醌、氧杂啉和甲萘醌对秀丽隐杆线虫的存活有不同的影响，并且未能激活培养的哺乳动物细胞中的 ARE 报告基因表达。我们的研究结果揭示了低剂量的天然萘醌通过参与特定的适应性细胞应激反应途径来延长寿命的潜力。 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。在这里，我们报道表达导致家族性PD的α-突触核蛋白突变体的小鼠表现出异常的心脏自主控制，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α-突触核蛋白积累相关。这些 ANS 异常发生在疾病过程的早期。高能量饮食会加剧β-突触核蛋白对心率控制的不利影响，而间歇性能量限制会改善这种不利影响。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。