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：
8931504
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
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/8931504
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 Image 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 National Institute of Drug Abuse 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 3xTgADmice 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. More recently we have collaborated with Hanbing Lu and Elliott Stein at NIDA to show that the default mode network can be imaged in mice and that its connectivity is altered in the 3xTgAD mosue model.

目前约有500万美国人患有阿尔茨海默氏病（AD），一种神经退行性疾病，其特征是认知功能以及情绪和睡眠障碍。该实验室已经开发了AD的细胞培养和小鼠模型，并使用这些模型阐明了导致AD中神经元功能障碍和死亡的生化和分子事件。我们的发现表明，由于细胞能量代谢受损和钙调节系统的不稳定，在衰老的神经元期间，神经元越来越容易发生功能障碍。淀粉样蛋白β-肽会加剧这些与年龄相关的神经元的变化，从而导致其变性并因此导致认知缺陷。膜脂质过氧化似乎在淀粉样蛋白前体蛋白的淀粉样生成加工中起重要作用，因为脂质过氧化产物4-羟基烯烯醇共价可修饰蛋白质NICASTRIN，从而增强γ-凝聚力酶活性。我们还发现，质膜中的氧化还原酶在保护神经元免受膜脂质过氧化和ABETA毒性方面起着重要作用。后一个发现揭示了以前未知的分子靶标，用于开发AD中新型治疗干预措施。我们发现，饮食限制可以减少淀粉样蛋白的沉积，并保护神经元免受AD动物模型受损和杀死的损害，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。抗抑郁剂5-羟色胺再摄取抑制剂可以减少淀粉样蛋白的沉积并改善AD小鼠模型中的认知功能，这表明潜在的预防性/治疗性使用此类药物。此外，我们发现一种称为二氮氧化物的药物先前用于治疗高血压，减少淀粉样蛋白和tau病理，并在我们的AD的3xTGAD小鼠模型中改善认知功能。此外，用烟酰胺补充烟酰胺在AD小鼠模型中通过涉及维持神经元能水平的机制以及增强淀粉样蛋白和TAU异常形式的清除的机制来抑制疾病过程。我们已经表明，糖尿病会导致认知功能的缺陷，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良反应。我们最近的发现表明，降低的GABA能抑制作用引起的兴奋性失衡是AD发病机理中的早期和关键事件。最近，我们证明了用于改善糖尿病和阿尔茨海默氏病动物模型中血糖控制的药物的治疗益处，并且我们在患有轻度认知障碍或早期阶段阿尔茨海默氏病的人类受试者中启动了其中一种药物的临床试验。脑能量代谢受损和氧化应激与认知下降以及淀粉样β肽（Aβ）和阿尔茨海默氏病（AD）中淀粉样β肽（Aβ）和高磷酸化的TAU的病理积累有关。为了确定改善大脑能量代谢是否会阻止AD的疾病进展，β-奈辛酰胺腺嘌呤二核苷酸前体烟酰胺对脑细胞线粒体功能和大噬菌学，生物能力相关的信号和认知性能的影响在培养的神经元和AD培养的神经元中研究了。氧化应激导致线粒体质量，线粒体变性和神经元中的自噬体积累。烟酰胺保留了线粒体完整性和自噬功能，并降低了神经元脆弱性对氧化/代谢损伤和Aβ毒性。烟酰胺的神经保护作用是烟酰胺的神经保护作用，需要β-烯丙胺腺苷二核苷酸生物合成，自噬和磷脂酰肌醇-3-激酶信号传导。用烟酰胺处理3 XTGADMICE 8个月可改善认知性能，并降低了海马和脑皮质中的Aβ和高磷酸化的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/自溶性酸化来减少自噬体积累，从而改善了自噬溶质体游治。用烟酰胺治疗3xTGAD小鼠会导致活化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）和转录因子环状腺苷单磷酸（AMP）单磷酸腺苷（AMP）响应元素结合蛋白质的蛋白质结合蛋白。因此，烟酰胺通过涉及改善线粒体和自噬系统功能的改善脑生物能的机制来抑制AD小鼠模型的AD病理和认知下降。阿尔茨海默氏病（AD）会恶化与年龄相关的睡眠失调。 AD和睡眠限制都损害了认知，但是尚不清楚轻度慢性睡眠限制是否会改变AD中涉及的蛋白质病过程。这项工作的目的是检验以下假设，即睡眠限制会使记忆力障碍恶化，淀粉样蛋白β-肽（Aβ）和PTAU在AD小鼠模型中积聚在大脑中，重点是循环糖皮质激素（GC）的作用。使用修改后的多个平台技术和行为（莫里斯水迷宫，恐惧调节，开放场）和生化（免疫印迹）结局，将男性3 XTGAD小鼠接受6小时/天的睡眠限制（SR）6小时，持续6周，将其与经过每日笼子转移的小鼠进行比较（大型笼子对照； LCC控制； LCC控制； LCC控制； LCC对照组）以及他们的控制（CAGE），以及他们的控制（CAGE）以及他们的控制（CAGE）。与CTL相比，在一周内，LCC和SR小鼠的血浆皮质酮均显示出显着升高（P <0.002）。到四个星期，与CTL相比，SR小鼠的循环皮质酮水平增加了两倍。行为数据表明在LCC或CTL不存在的SR小鼠中的上下文记忆中缺陷（P <0.04）。与CTL和LCC相比，SR小鼠皮层的Aβ和PTAU水平都升高。但是，海马中未注意到这些变化。皮质Aβ与PTAU水平与循环皮质酮之间的显着正相关表明，GC在介导AD小鼠模型中睡眠限制后观察到的行为和生化变化的潜在作用。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。最近，我们与NIDA的Hanbing Lu和Elliott Stein合作，以表明可以在小鼠中成像默认模式网络，并且在3xtgad Mosue模型中其连通性已更改。