Metabolism of Alzheimer’s Disease: systems and cellular networks

阿尔茨海默病的代谢：系统和细胞网络

• 批准号: 10407033
• 负责人: Rozalyn M. Anderson
• 金额: $ 66.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407033
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Astrocytes; Attenuated; Behavior; Biology; Biology of Aging; Blood Vessels; Blood flow; Brain; Caloric Restriction; Cell Communication; Cells; Clinical; Communication; Complement; Coupled; Detection; Development; Disease; Disease Progression; Electrodes; Electrophysiology (science); Energy Metabolism; Environment; Etiology; Gene Expression; Geroscience; Hippocampus (Brain); Histocytochemistry; Image; Imaging technology; Impaired cognition; Implant; Individual; Intervention; Measures; Memory; Metabolic; Metabolism; Mitochondria; Modeling; Monkeys; Morphology; Mus; Neurofibrillary Tangles; Neuroglia; Neurons; Outcome; Oxidation-Reduction; Pathology; Pattern; Pharmacology; Play; Prevalence; Proteomics; Research; Role; Senile Plaques; Signal Transduction; Synapses; Synaptic Transmission; System; Tauopathies; Techniques; Testing; Therapeutic; Time; Tissues; Translating; United States; Work; age related; aging brain; anti aging; astrogliosis; behavior test; brain cell; brain metabolism; brain volume; burden of illness; cranium; density; effective therapy; experimental study; genetic approach; hyperphosphorylated tau; imaging study; in vivo; in vivo imaging; insight; live cell imaging; metabolic imaging; microscopic imaging; mouse model; neuroprotection; optogenetics; patch clamp; preservation; response; tau mutation; tomography; trend; two-photon

ABSTRACT Alzheimer's disease (AD) is increasing in prevalence in the United States and despite efforts to date an effective treatment remains elusive. AD presents clinically as amyloid plaque load, neurofibrillary tangles comprised of hyper phosphorylated tau, and abnormal vasculature, but the mechanistic basis for cognitive decline is not known. We have shown that the anti-aging intervention of caloric restriction (CR) preserves brain volume and neuronal synaptic density, and lowers age-related astrogliosis. Importantly, age-related shifts in redox metabolism and mitochondrial energy metabolism in brain are abrogated by CR. Our hypothesis is that neuroprotection by CR will slow AD pathology development specifically through its impact on brain metabolism. We will implement CR in APP PS1 (amyloid plaques) and hTauP301 (neurofibrillary tangles) mouse models of AD to determine the impact of CR-induced changes in brain metabolism on pathology development and the consequence for cellular networks of neurons, glia, and the vasculature. Experiments include behavioral testing, ex vivo electrophysiology, and in vivo imaging technology. Brain metabolism will be tracked using histochemistry and 2-photon metabolic imaging. Additional mechanistic studies using pharmacological and genetic approaches in primary neurons and astrocytes will determine the impact of metabolism on brain cell-cell networks. There are three specific aims: Specific Aim 1: To determine the impact of CR on AD pathology advance, documenting hippocampal dependent memory and behaviors, ex vivo measures of synaptic transmission and hippocampal neuronal networks, and brain metabolism. Specific Aim 2: To determine the impact of metabolism and AD pathology on neuron-glial crosstalk using co-cultured primary neurons and primary astrocytes. Live imaging studies will investigate how neurons with amyloidopathy and tauopathy respond to changes in astrocyte metabolism in real time. Specific Aim 3: To determine the in vivo impact of CR-induced changes in brain metabolism and AD pathology on vascular responsivity and adaptation using implanted transparent electrodes and opto-genetics coupled with coherence tomography. These studies focus on the interaction between disease pathology and the local brain metabolic environment, acknowledging the importance of layers of communication among neuronal, neuron-glia, and vascular networks, and establishing mechanisms behind the neuroprotective effects of CR. The proposed research will advance our understanding of the role metabolism plays in AD progression, and will determine if strategies to preserve brain metabolism as a function of age might have therapeutic potential as a means to ameliorate outcomes of AD, translating basic biology to clinical promise.

抽象的 阿尔茨海默氏病（AD）在美国的患病率正在增加，尽管有效努力 治疗仍然难以捉摸。广告在临床上作为淀粉样菌斑负荷呈现，神经纤维缠结由 超磷酸化的tau和异常的脉管系统，但认知能力下降的机理基础不是 已知。我们已经表明，热量限制（CR）的抗衰老干预可保留大脑体积和 神经元突触密度，并降低与年龄有关的星形胶质细胞增多症。重要的是，氧化还原与年龄相关的变化 CR废除了大脑中的代谢和线粒体能量代谢。我们的假设是 CR神经保护将通过其对脑代谢的影响特别减慢AD病理发展。 我们将在App PS1（淀粉样蛋白斑块）和HTAUP301（神经原纤维缠结）的鼠标模型中实现CR AD确定CR诱导的脑代谢变化对病理发展的影响 神经元，神经胶质和脉管系统的细胞网络的结果。实验包括行为测试， 离体电生理学和体内成像技术。将使用组织化学跟踪脑代谢 和2光子代谢成像。使用药理和遗传学方法的其他机械研究 在原发性神经元和星形胶质细胞中，将决定代谢对脑细胞网络网络的影响。有 三个具体目标： 特定目的1：确定CR对AD病理学的影响，记录海马 依赖记忆和行为，突触传播的离体测量和海马神经元 网络和大脑代谢。 特定目的2：确定新陈代谢和AD病理对使用神经元串扰的影响 共培养的原发性神经元和原代星形胶质细胞。实时成像研究将研究神经元如何与 淀粉样蛋白病和陶氏疗法对星形胶质细胞代谢的变化作出反应。 特定目的3：确定CR诱导的脑代谢变化和AD变化的体内影响 使用植入的透明电极和光学生殖器的血管反应性和适应性的病理 再加上连贯的断层扫描。 这些研究重点是疾病病理与局部脑代谢之间的相互作用 环境，承认神经元，神经元 - 神经元和 血管网络，并在CR的神经保护作用背后建立机制。提议 研究将促进我们对代谢在AD进展中所扮演的作用的理解，并将确定是否是否 保存大脑代谢随着年龄的影响的策略可能具有治疗潜力作为一种手段 改善AD的结果，将基本生物学转化为临床承诺。