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.

在正常衰老过程中，灵长类动物背外侧前额皮质（LPFC）中的锥体细胞经历了显着的变化。与初级视觉皮层中的锥体细胞的结构和功能变化有关。 (V1) 相对幸免于该补充的父项目 (R01 AG059028) 嵌套了选择性。与衰老恒河猴的 V1 相比，LPFC 中神经元和相关网络的脆弱性，以及年龄相关的氧化应激、炎症和血管功能障碍在高易感性人群中的作用我们还提出姜黄素（一种抗氧化剂和抗炎多酚）可以改善 LPFC 神经元。我们使用最先进的独特组合来治疗与年龄相关的分子、结构和行为变化。生理学、解剖学和计算方法以及衰老猴子的行为评估，控制病情并进行姜黄素治疗后的应用（PA-18-591）。通过评估细胞改变和神经元，代表了这项工作对人脑的逻辑延伸与神经正常对照个体相比，死后大脑因阿尔茨海默病（AD）而死亡。重点关注 AD 中严重且优先脆弱的大锥体神经元子集，可通过高去磷酸化神经丝蛋白的含量，位于灵长类动物的深层 3 和层 5。先前的分析表明，这些神经元在 AD 早期阶段以更快的速度形成缠结与其他锥体细胞相比，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来分析 AD 病例中这些神经元的分子表型与对照组（CDR 0）相比，患有早期（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质神经亚群的蛋白质表达谱通过在同一组织切片上对大量生物标志物进行成像，人类大脑和 AD 进展过程中，能够逐个细胞地对细胞类型和状态进行分类。将用于根据分子表型分配神经亚类我们将分析区域 9/46。 (LPFC)，在 AD 中受到影响，以及 17 (V1)，在 AD 中通常不受影响，复制了实验父项目的设计。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，以及我们期望在层层分辨率上揭示潜在的诊断和治疗。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本补充及其父项目将产生新颖且关键的成果。有关衰老灵长类动物认知能力下降的神经基础的信息，并提供对特定保护性抗炎和抗氧化剂在正常和病理性脑衰老中的作用机制。