Mechanisms of Age-related Cognitive Decline in the Rhesus Monkey

恒河猴与年龄相关的认知衰退的机制

• 批准号: 9717436
• 负责人: PATRICK R HOF
• 金额: $ 48.8万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9717436
• 关键词: Action Potentials; Address; Adult; Affect; Age-associated memory impairment; Aging; Algorithms; Alzheimer' s Disease; Amyloid deposition; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Area; Autopsy; Back; Behavior; Behavior assessment; Behavioral; Biological Markers; Blood Vessels; Brain; Brain Diseases; Brain region; Catalogs; Cell physiology; Cells; Classification; Clinical; Cognitive; Cognitive deficits; Computer Simulation; Curcumin; Cytopathology; Data; Dementia; Dendritic Spines; Detection; Development; Diagnostic; Disease; Disease Progression; Early Diagnosis; Electron Microscopy; Environment; Exhibits; Experimental Designs; Expression Profiling; Goals; Human; Image; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Impaired cognition; In Situ; In Vitro; Individual; Inflammation; Inflammatory; Interneurons; Intervention; Lateral; Longevity; Macaca mulatta; Machine Learning; Membrane; Methods; Mitochondria; Modeling; Molecular; Molecular Profiling; Molecular Target; Monkeys; Morphology; Neocortex; Neurofibrillary Tangles; Neurofilament Proteins; Neuroglia; Neurons; Neuropil; Neurotransmitter Receptor; Oxidative Stress; Parents; Pathologic; Pathology; Pathway interactions; Pattern; Physiological; Predisposition; Prefrontal Cortex; Prevention; Primates; Property; Proteins; Pyramidal Cells; Reaction; Resolution; Role; Sampling; Short-Term Memory; Signal Transduction; Slice; Stimulus; Supervision; Symptoms; Synapses; Techniques; Testing; Therapeutic; Tissues; V1 neuron; Vascular Diseases; Visual Cortex; Visuospatial; Work; age related; aged; aging brain; aging population; area striata; base; brain dysfunction; cell type; comparative; cytokine; density; design; extracellular; hippocampal pyramidal neuron; insight; middle age; molecular marker; molecular phenotype; neocortical; network models; neurofibrillary tangle formation; normal aging; novel; novel strategies; parent project; patch clamp; polyphenol; postsynaptic; prevent; protein biomarkers; protein expression; relating to nervous system; therapeutic target

During normal aging, pyramidal cells in the primate dorsolateral prefrontal cortex (LPFC) undergo significant structural and functional changes associated with cognitive deficits. Pyramidal cells in the primary visual cortex (V1) are comparatively spared. The parent project of this Supplement (R01 AG059028) analyzes the selective vulnerability of neurons and associated networks in LPFC compared to V1 in aging rhesus monkeys, and the role of age-related increases in oxidative stress, inflammation, and vascular dysfunction in high-susceptibility LPFC neurons. We also propose that curcumin, an antioxidant and anti-inflammatory polyphenol, ameliorates age-related molecular, structural, and behavioral changes. We use a unique combination of state-of-the art physiological, anatomical and computational approaches, and behavioral assessment of aging monkeys, under control conditions and following therapeutic treatment with curcumin. This Supplement application (PA-18-591) represents a logical extension of this work to the human brain by assessing cellular alterations and neuronal demise in postmortem brains from Alzheimer’s disease (AD) compared to neurotypical control individuals. We focus on subsets of large pyramidal neurons severely and preferentially vulnerable in AD, identifiable by a high content of dephosphorylated neurofilament proteins and located in deep layer 3 and layer 5 in primates. Our previous analyses revealed that these neurons undergo tangle formation in early stages of AD at a faster rate than other pyramidal cells. We will use the same highly multiplexed quantitative immunofluorescence platform together with rigorous stereologic designs to analyze the molecular phenotype of these neurons in AD cases with early (Clinical Dementia Scores [CDR] 0.5) and definite (CDR 3) dementia compared to controls (CDR 0). We will characterize in detail the protein expression profiles of neocortical neuron subsets in the normally aging human brain and through AD progression by imaging on the same tissue section large numbers of biomarkers, enabling classification of cell types and states on a cell-by-cell basis. Data-driven machine-learning techniques will be applied to assign neuronal subclasses based on molecular phenotype. We will analyze areas 9/46 (LPFC), which is affected in AD, and 17 (V1), which is generally spared in AD, replicating the experimental design of the parent project. Using many molecular markers from the parent project, we will study the microenvironment of vulnerable and non-vulnerable neurons, including glial and vascular cells, and extracellular pathology, at a layer-level of resolution. We expect to uncover potential diagnostic and therapeutic targets that could ultimately provide new approaches for earlier disease detection and prevention of progressive loss of critical neurons in AD. This Supplement and its parent project will yield novel and key information on the neural substrates of cognitive decline in aging primates and provide insight into specific mechanisms of action of protective anti-inflammatory and anti-oxidants in normal and pathological brain aging.

在正常衰老过程中，灵长类动物背外侧前额叶皮层（LPFC）的锥体细胞经历了显著的 与认知缺陷相关的结构和功能变化。初级视皮层的锥体细胞 (V1)相对来说，他们是不受影响的。本补充文件的父项目（R01 AG059028）分析了 与老龄恒河猴V1相比，LPFC中神经元和相关网络的脆弱性，以及 与年龄相关的氧化应激、炎症和血管功能障碍在高易感性中的作用 LPFC神经元。我们还提出，姜黄素，抗氧化剂和抗炎多酚，改善 与年龄相关的分子、结构和行为变化。我们使用了最先进的 生理学、解剖学和计算方法，以及衰老猴子的行为评估， 对照条件和随后用姜黄素治疗性处理。本补充申请（PA-18 - 591） 通过评估细胞变化和神经元变化， 死亡在死后的大脑从阿尔茨海默氏病（AD）相比，神经典型的控制个人。我们 重点关注在AD中严重和优先脆弱的大锥体神经元的子集，可通过高 在灵长类动物中，去磷酸化神经丝蛋白的含量最高，位于深层3和深层5。我们 先前的分析显示，这些神经元在AD的早期阶段以更快的速度进行缠结形成， 比其他的锥体细胞要多。我们将使用相同的高度多重定量免疫荧光平台 结合严格的体视学设计，分析AD病例中这些神经元的分子表型 与对照组（CDR 0）相比，早期（临床痴呆评分[CDR] 0.5）和明确（CDR 3）痴呆。 我们将详细描述正常衰老过程中新皮层神经元亚群的蛋白质表达谱 人脑和通过在同一组织切片上成像大量生物标志物的AD进展， 使得能够在逐个细胞的基础上对细胞类型和状态进行分类。数据驱动的机器学习技术 将应用于分配神经元亚类的分子表型的基础上。我们将分析9/46区域 （LPFC），其在AD中受影响，和17（V1），其通常在AD中不受影响，复制了实验性 父项目的设计。使用来自母项目的许多分子标记，我们将研究 脆弱和非脆弱神经元的微环境，包括神经胶质细胞和血管细胞，以及 细胞外病理学，在一个层次的分辨率。我们希望发现潜在的诊断和治疗 这些目标最终可以为早期疾病检测和预防提供新的方法， AD中关键神经元的进行性丢失。这个补充和它的父项目将产生新的和关键的 关于衰老灵长类动物认知能力下降的神经基质的信息，并提供了对特定 保护性抗炎和抗氧化剂在正常和病理性脑老化中的作用机制。