Metabolism of Alzheimer’s Disease: systems and cellular networks

摘要 阿尔茨海默病(AD)在美国的患病率正在上升，尽管人们努力寻找有效的治疗方法 治疗方法仍然难以捉摸。AD的临床表现为淀粉样斑块负载，神经原纤维缠结由 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 为人所知。我们已经证明，卡路里限制(CR)的抗衰老干预保留了脑容量和 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的神经保护将减缓AD的病理发展，特别是通过其对大脑代谢的影响。 我们将在APP PS1(淀粉样斑块)和hTauP301(神经原纤维缠结)小鼠模型中实现CR AD以确定CR引起的脑代谢改变对病理发展的影响 对神经元、神经胶质细胞和血管系统的细胞网络的影响。实验包括行为测试， 体外电生理学和体内成像技术。将使用组织化学来跟踪大脑新陈代谢 和双光子代谢成像。使用药理学和遗传学方法进行的其他机制研究 原代神经元和星形胶质细胞将决定新陈代谢对脑细胞-细胞网络的影响。确实有 三个具体目标： 具体目标1：确定CR对AD病理进展的影响，记录海马区 依存性记忆和行为、突触传递和海马神经元的体外测量 网络和大脑新陈代谢。 特定目标2：确定代谢和AD病理对神经元-神经胶质细胞串扰的影响 共培养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 淀粉样变性和肌萎缩侧索硬化症对星形胶质细胞代谢的变化做出实时反应。 具体目标3：确定CR引起的脑代谢改变和AD的体内影响 植入透明电极的血管反应性和适应性的病理学和光遗传学 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，认识到神经元、神经元-胶质细胞和 血管网络，以及建立CR神经保护作用背后的机制。建议数 研究将促进我们对新陈代谢在AD进展中所起作用的理解，并将确定 保持大脑新陈代谢随年龄增长的策略可能具有治疗潜力，作为一种手段 改善阿尔茨海默病的预后，将基础生物学转化为临床前景。

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.