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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

在正常衰老期间，原发性双层质额叶皮层（LPFC）中的锥体细胞发生显着与认知缺陷相关的结构和功能变化。一级视觉皮层中的锥体细胞（V1）相对幸免。该补充剂的父项目（R01 AG059028）分析了选择性与老化的恒河猴和V1相比，LPFC中神经元和相关网络的脆弱性，与年龄相关的作用在氧化应激，感染和血管功能障碍中的作用在高抑制性中的作用 LPFC神经元。我们还建议姜黄素，一种抗氧化剂和抗炎多酚，可以改善与年龄相关的分子，结构和行为变化。我们使用最先进的独特组合生理，解剖学和计算方法以及衰老猴子的行为评估控制条件并在用姜黄素治疗后进行治疗。此补充申请（PA-18-591）通过评估细胞改变和神经元，代表了这项工作向人脑的逻辑扩展与神经型对照个体相比，阿尔茨海默氏病（AD）死后大脑的灭亡。我们专注于大型锥体神经元的子集严重而优先脆弱的AD，可通过高识别去磷酸化的神经丝蛋白的含量，位于初级的第3层和第5层中。我们的先前的分析表明，这些神经元在AD的早期阶段经历缠结形成，以更快的速度比其他锥体细胞。我们将使用相同高度多重的定量免疫荧光平台以及严格的立体设计，以分析AD病例中这些神经元的分子表型与对照组（CDR 0）相比，具有早期（临床痴呆评分[CDR] 0.5）并定义（CDR 3）痴呆。我们将详细描述正常衰老中新皮质神经元子集的蛋白质表达谱人脑和通过在同一组织部分成像大量生物标志物通过成像，逐个细胞基于细胞类型和状态的分类。数据驱动的机器学习技术将应用于基于分子表型的神经元亚类。我们将分析9/46区域（LPFC），在AD中受到影响，17（V1），通常在AD中保留，复制实验父项目的设计。使用父项目中的许多分子标记，我们将研究易受伤害和不可吸收神经元的微环境，包括神经胶质和血管细胞，以及细胞外病理，在分辨率的层面上。我们希望发现潜在的诊断和治疗最终可以为早期疾病检测和预防提供新方法的目标 AD中关键神经元的逐渐丧失。这种补充及其父母项目将产生小说和关键有关衰老隐私性认知能力下降的神经基质的信息，并提供对特定的洞察力在正常和病理大脑衰老中保护性抗炎和抗氧化剂的作用机制。