Cellular And Molecular Pathogenesis Of Alzheimer

阿尔茨海默病的细胞和分子发病机制

基本信息

批准号：
8736517
负责人：
Mark Mattson
金额：
$ 79.05万
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/8736517
关键词：
1-Phosphatidylinositol 3-Kinase 3-Phosphoinositide Dependent Protein Kinase-1 4 hydroxynonenal Adverse effects Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model American Amygdaloid structure Amyloid Amyloid beta-Protein Amyloid deposition Anabolism Animal Model Antidepressive Agents Anxiety Autophagocytosis Autophagosome Autopsy Behavioral Binding Proteins Biochemical Bioenergetics Brain Brain region Brain-Derived Neurotrophic Factor Calcium Carbohydrates Cell Culture Techniques Cell membrane Cerebral cortex Cessation of life Chronic Clinical Trials Cognitive Cognitive deficits Corticosterone Cues Cyclic AMP Data Deposition Development Diabetes Mellitus Diazoxide Diet Dietary Supplementation Disease Drug usage Emotional Disturbance Energy Metabolism Enzymes Esters Event Exercise Exhibits Functional disorder Glucocorticoids Glucose Goals Hippocampus (Brain)Home environment Hypertension Immunoblotting Impaired cognition Impairment Ketone Bodies Ketones Knowledge Laboratories Learning Lipid Peroxidation Lysosomes Mediating Membrane Lipids Memory Memory impairment Metabolic Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neuronal Plasticity Neurons Niacinamide Nicotinamide adenine dinucleotide Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Pathologic Pathology Patients Performance Pharmaceutical Preparations Physiological Plasma Play Process Production Response Elements Role Selective Serotonin Reuptake Inhibitor Signal Transduction Sleep Sleep disturbances Staging Synaptic plasticity System Techniques Testing Therapeutic Therapeutic Intervention Therapeutic Uses Toxic effect Work abeta toxicity age related amyloid precursor protein processing base behavior test brain cell brain tissue cognitive function conditioned fear dietary restriction exenatide feeding gamma secretase glycemic control human subject hyperphosphorylated tau improved killings male men&apos s group mild cognitive impairment morris water maze mouse model neurogenesis nicastrin protein novel novel therapeutic intervention peptide A prophylactic tau Proteins transcription factor

项目摘要

Approximately 5 million Americans currently suffer from Alzheimers disease (AD) a neurodegenerative disorder characterized by progressive impairment of cognitive function and emotional and sleep disturbances. This laboratory has developed cell culture and mouse models of AD, and have used these models to elucidate the biochemical and molecular events responsible for neuronal dysfunction and death in AD. Our findings suggest that during aging neurons become increasingly prone to dysfunction as a result of impaired cellular energy metabolism and destabilization of calcium-regulating systems. Amyloid beta-peptide can exacerbate these age-related changes in neurons resulting in their degeneration and consequent cognitive deficits. Membrane lipid peroxidation appears to play an important role in amyloidogenic processing of the amyloid precursor protein as the lipid peroxidation product 4-hydroxynonenal covalently modifies the protein nicastrin and thereby increases gamma-secretase activity. We have also found that redox enzymes in the plasma membrane play important roles in protecting neurons against membrane lipid peroxidation and Abeta toxicity. The latter findings reveal previously unknown molecular targets for the development of novel therapeutic interventions in AD. We have found that dietary restriction can reduce amyloid deposition and protect neurons from being damaged and killed in animal models of AD, and that this beneficial effect of dietary restriction involves stimulation of the production of brain-derived neurotrophic factor (BDNF). Antidepressant serotonin reuptake inhibitors can reduce amyloid deposition and improve cognitive function in a mouse model of AD, suggesting a potential prophylactic/therapeutic use of such drugs. In addition, we found that a drug called diazoxide, previously used to treat hypertension,reduces amyloid and tau pathologies and improves cognitive function in our 3xTgAD mouse model of AD. In addition, dietary supplementation with nicotinamide retards the disease process in a mouse model of AD by a mechanism involving sustenance of neuronal energy levels and enhanced clearance of abnormal forms of amyloid and tau. We have shown that diabetes causes a deficit in cognitive function which is associated with impaired hippocampal synaptic plasticity and neurogenesis; exercise and dietary energy restriction can counteract these adverse effects of diabetes. Our recent findings suggest that an excitatory imbalance, resulting from reduced GABAergic inhibition, is an early and pivotal event in AD pathogenesis. We recently demonstrated a therapeutic benefit of drugs used to improve glycemic control in animal models of diabetes and Alzheimer's disease, and we have initiated a clinical trial of one of these drugs, Exenatide, in human subjects with mild cognitive impairment or early stage Alzheimer's disease. Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated tau in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the β-nicotinamide adenine dinucleotide precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling, and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration, and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and Aβ toxicity. β-Nicotinamide adenine dinucleotide biosynthesis, autophagy, and phosphatidylinositol-3-kinase signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced Aβ and hyperphosphorylated tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (protein kinase B Akt and extracellular signal-regulated kinases) and the transcription factor cyclic adenosine monophosphate (AMP) response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system. Age-associated dysregulation of sleep can be worsened by Alzheimer's disease (AD). AD and sleep restriction both impair cognition, yet it is unknown if mild chronic sleep restriction modifies the proteopathic processes involved in AD. The goal of this work was to test the hypothesis that sleep restriction worsens memory impairments, and amyloid β-peptide (Aβ) and pTau accumulations in the brain in a mouse model of AD, with a focus on a role for circulating glucocorticoids (GC). Male 3xTgAD mice were subjected to sleep restriction (SR) for 6h/day for 6 weeks using the modified multiple platform technique, and behavioral (Morris water maze, fear conditioning, open field) and biochemical (immunoblot) outcomes were compared to mice undergoing daily cage transfers (large cage control; LCC) as well as control mice that remained in their home cage (control; CTL). At one week, both LCC and SR mice displayed significant elevations in plasma corticosterone compared to CTL (p<0.002). By four weeks, SR mice displayed a two-fold increase in circulating corticosterone levels compared to CTL. Behavioral data indicated deficits in contextual and cued memory in SR mice that were not present for LCC or CTL (p<0.04). Both Aβ and pTau levels increased in the cortex of SR mice compared to CTL and LCC; however these changes were not noted in the hippocampus. Significant positive correlations between cortical Aβ and pTau levels and circulating corticosterone indicate a potential role for GCs in mediating behavioral and biochemical changes observed after sleep restriction in a mouse model of AD. 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.

目前大约有 500 万美国人患有阿尔茨海默病 (AD)，这是一种神经退行性疾病，其特征是认知功能进行性损害以及情绪和睡眠障碍。该实验室开发了 AD 细胞培养和小鼠模型，并利用这些模型来阐明导致 AD 神经元功能障碍和死亡的生化和分子事件。我们的研究结果表明，在衰老过程中，由于细胞能量代谢受损和钙调节系统不稳定，神经元变得越来越容易出现功能障碍。 β-淀粉样肽会加剧神经元中这些与年龄相关的变化，导致神经元退化和随之而来的认知缺陷。膜脂质过氧化似乎在淀粉样前体蛋白的淀粉样变性加工中发挥重要作用，因为脂质过氧化产物4-羟基壬烯醛共价修饰蛋白质烟碱，从而增加γ-分泌酶活性。我们还发现质膜中的氧化还原酶在保护神经元免受膜脂过氧化和 Abeta 毒性方面发挥着重要作用。后者的发现揭示了以前未知的用于开发 AD 新型治疗干预措施的分子靶点。我们发现，在 AD 动物模型中，饮食限制可以减少淀粉样蛋白沉积，保护神经元免受损伤和杀死，并且饮食限制的这种有益作用涉及刺激脑源性神经营养因子 (BDNF) 的产生。抗抑郁药血清素再摄取抑制剂可以减少 AD 小鼠模型中的淀粉样蛋白沉积并改善认知功能，表明此类药物具有潜在的预防/治疗用途。此外，我们发现一种名为二氮嗪的药物（以前用于治疗高血压）可减少淀粉样蛋白和 tau 蛋白病理，并改善我们的 3xTgAD AD 小鼠模型的认知功能。此外，膳食补充烟酰胺可通过维持神经元能量水平和增强异常形式淀粉样蛋白和 tau 蛋白的清除机制来延缓 AD 小鼠模型的疾病进程。我们已经证明，糖尿病会导致认知功能缺陷，这与海马突触可塑性和神经发生受损有关。运动和饮食能量限制可以抵消糖尿病的这些不利影响。我们最近的研究结果表明，GABA 能抑制减少导致的兴奋性失衡是 AD 发病机制的早期关键事件。我们最近证明了用于改善糖尿病和阿尔茨海默病动物模型血糖控制的药物的治疗益处，并且我们已经在患有轻度认知障碍或早期阿尔茨海默病的人类受试者中启动了其中一种药物艾塞那肽的临床试验。大脑能量代谢受损和氧化应激与阿尔茨海默病 (AD) 中的认知能力下降以及淀粉样 β-肽 (Aβ) 和过度磷酸化 tau 蛋白的病理性积累有关。为了确定改善脑能量代谢是否会阻止 AD 疾病的进展，在培养的神经元和小鼠中研究了 β-烟酰胺腺嘌呤二核苷酸前体烟酰胺对脑细胞线粒体功能和巨自噬、生物能相关信号传导和认知能力的影响AD模型。氧化应激导致神经元中线粒体质量减少、线粒体变性和自噬体积累。烟酰胺保留了线粒体的完整性和自噬功能，并降低了神经元对氧化/代谢损伤和 Aβ 毒性的脆弱性。烟酰胺的神经保护作用需要β-烟酰胺腺嘌呤二核苷酸生物合成、自噬和磷脂酰肌醇-3-激酶信号传导。用烟酰胺治疗 3xTgAD 小鼠 8 个月，可改善认知能力，并减少海马和大脑皮层的 Aβ 和过度磷酸化 tau 病理。烟酰胺处理保留了线粒体完整性，并通过增强溶酶体/自溶酶体酸化以减少自噬体积累来改善自噬-溶酶体加工。用烟酰胺治疗 3xTgAD 小鼠会导致海马和大脑皮层中激活的神经可塑性相关激酶（蛋白激酶 B Akt 和细胞外信号调节激酶）以及转录因子环磷酸腺苷 (AMP) 反应元件结合蛋白的水平升高。因此，烟酰胺通过一种涉及改善大脑生物能学并保留线粒体和自噬系统功能的机制来抑制 AD 小鼠模型的 AD 病理学和认知能力下降。阿尔茨海默病 (AD) 可能会加剧与年龄相关的睡眠失调。 AD 和睡眠限制都会损害认知，但尚不清楚轻微的慢性睡眠限制是否会改变 AD 所涉及的蛋白质病理过程。这项工作的目的是检验这样的假设：在 AD 小鼠模型中，睡眠限制会加剧记忆障碍以及淀粉样蛋白 β 肽 (Aβ) 和 pTau 在大脑中的积累，重点是循环糖皮质激素 (GC) 的作用。使用改良的多平台技术对雄性 3xTgAD 小鼠进行每天 6 小时的睡眠限制 (SR)，持续 6 周，并将行为（莫里斯水迷宫、恐惧调节、开放场）和生化（免疫印迹）结果与每天接受睡眠限制 (SR) 的小鼠进行比较笼转移（大笼对照；LCC）以及留在其家笼中的对照小鼠（对照；CTL）。一周后，与 CTL 相比，LCC 和 SR 小鼠的血浆皮质酮均显着升高（p<0.002）。四周时，SR 小鼠的循环皮质酮水平比 CTL 增加两倍。行为数据表明 SR 小鼠存在情境记忆和线索记忆缺陷，而 LCC 或 CTL 则不存在这种缺陷（p<0.04）。与 CTL 和 LCC 相比，SR 小鼠皮质中的 Aβ 和 pTau 水平均有所增加；然而，海马体中没有注意到这些变化。皮质 Aβ 和 pTau 水平与循环皮质酮之间的显着正相关表明 GC 在调节 AD 小鼠模型睡眠限制后观察到的行为和生化变化中具有潜在作用。阿尔茨海默病 (AD) 涉及β-淀粉样肽 (Aβ) 的逐渐积累和神经原纤维病变，以及对记忆至关重要的大脑区域的葡萄糖代谢减退。 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 喂养的小鼠在下托、海马 CA1 和 CA3 区域以及杏仁核中的 Aβ 沉积减少。 KET 喂养的小鼠在海马体、杏仁核和皮质的相同区域表现出过度磷酸化 tau 沉积水平降低。因此，一种新型酮酯可以改善小鼠 AD 模型中的蛋白质病理和行为缺陷。