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: 10634691
• 负责人: Rozalyn M. Anderson
• 金额: $ 65.99万
• 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/10634691
• 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; Coculture Techniques; Communication; Complement; Coupled; Detection; Development; Disease; Disease Progression; Electrodes; Electrophysiology (science); Energy Metabolism; Environment; Etiology; Gene Expression; Geroscience; Hippocampus; 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; 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; imaging study; in vivo; in vivo imaging; insight; live cell imaging; metabolic imaging; microscopic imaging; mouse model; neuroprotection; optogenetics; patch clamp; pharmacologic; preservation; response; tau-1; 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.

摘要 阿尔茨海默氏病（AD）在美国的患病率正在增加，尽管迄今为止已经做出了有效的治疗措施， 治疗仍然难以捉摸。AD在临床上表现为淀粉样斑块负荷，神经系统缠结，包括 过度磷酸化的tau蛋白和异常的血管系统，但认知能力下降的机制基础不是 知道的我们已经证明，热量限制（CR）的抗衰老干预可以保留脑容量， 神经元突触密度，并降低年龄相关的星形胶质细胞增生。重要的是，与年龄相关的氧化还原变化 CR可抑制脑内代谢和线粒体能量代谢。我们的假设是 CR的神经保护作用将减缓AD病理学发展，特别是通过其对脑代谢的影响。 我们将在APP PS1（淀粉样斑块）和hTauP 301（神经元缠结）小鼠模型中实施CR， AD，以确定CR诱导的脑代谢变化对病理学发展的影响， 神经元、神经胶质和脉管系统的细胞网络的后果。实验包括行为测试， 离体电生理学和体内成像技术。将使用组织化学追踪脑代谢 和双光子代谢成像。使用药理学和遗传学方法的其他机制研究 在初级神经元和星形胶质细胞中的作用将决定代谢对脑细胞-细胞网络的影响。有 三个具体目标： 具体目标1：确定CR对AD病理进展的影响，记录海马 依赖性记忆和行为，突触传递和海马神经元的离体测量 网络和大脑代谢。 具体目标2：使用以下方法确定代谢和AD病理学对神经元-胶质细胞串扰的影响： 共培养的原代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tau蛋白病对星形胶质细胞代谢的变化有真实的反应。 具体目标3：确定CR诱导的脑代谢变化和AD的体内影响 使用植入透明电极和光遗传学对血管反应性和适应性的病理学研究 再加上相干断层扫描 这些研究集中在疾病病理和局部脑代谢之间的相互作用 环境，承认神经元，神经胶质细胞， 血管网络，并建立机制背后的CR的神经保护作用。拟议 研究将促进我们对代谢在AD进展中所起作用的理解，并将确定 保护大脑代谢作为年龄函数的策略可能具有治疗潜力， 改善AD的结果，将基础生物学转化为临床承诺。

项目成果

Resilience integrates concepts in aging research.

• DOI: 10.1016/j.isci.2022.104199
• 发表时间: 2022-05-20
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Promislow, Daniel;Anderson, Rozalyn M.;Scheffer, Marten;Crespi, Bernard;DeGregori, James;Harris, Kelley;Horowitz, Barbara Natterson;Levine, Morgan E.;Riolo, Maria A.;Schneider, David S.;Spencer, Sabrina L.;Valenzano, Dario Riccardo;Hochberg, Michael E.
• 通讯作者: Hochberg, Michael E.

Optimal data acquisition in tomography.

断层扫描中的最佳数据采集。

• DOI: 10.1364/josaa.506113
• 发表时间: 2023
• 期刊: Journal of the Optical Society of America. A, Optics, image science, and vision
• 作者: Javidan,Mahshad;Esfandi,Hadi;Anderson,Rozalyn;Pashaie,Ramin
• 通讯作者: Pashaie,Ramin

CSF metabolites associated with biomarkers of Alzheimer's disease pathology.

• DOI: 10.3389/fnagi.2023.1214932
• 发表时间: 2023
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8

Taking the long view on metabolism.

从长远的角度看待新陈代谢。

• DOI: 10.1126/science.abl4537
• 发表时间: 2021
• 期刊: Science (New York, N.Y.)
• 作者: Rhoads,TimothyW;Anderson,RozalynM
• 通讯作者: Anderson,RozalynM

Alpha-Ketoglutarate, the Metabolite that Regulates Aging in Mice.

• DOI: 10.1016/j.cmet.2020.08.009
• 发表时间: 2020-09-01
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Rhoads TW;Anderson RM
• 通讯作者: Anderson RM