Mechanisms of Age-related Cognitive Decline in the Rhesus Monkey

在正常衰老期间，灵长类动物背外侧前额叶皮质中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。初级视皮层中的锥体细胞 (V1)相对幸免于难。本附录的父项目(R01 AG059028)分析了可选的 与V1相比，LPFC中神经元和相关网络在衰老恒河猴中的脆弱性，以及 年龄相关性氧化应激、炎症和血管功能障碍在高易感人群中的作用 LPFC神经元。我们还提出，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。我们使用了独特的最先进的组合 生理学、解剖学和计算方法，以及对衰老猴子的行为评估，在 控制条件和随后的姜黄素治疗。本补充申请(PA-18-591) 通过评估细胞变化和神经元的变化，代表了这项工作在人脑中的合理延伸 与神经典型对照组相比，阿尔茨海默病(AD)死后大脑的死亡。我们 重点关注AD中严重且优先易受攻击的大锥体神经元的亚群，可通过高 去磷酸化的神经丝蛋白在灵长类动物中的含量，位于深层3层和5层。我们的 先前的分析表明，这些神经元在AD的早期阶段以更快的速度形成缠结 而不是其他锥体细胞。我们将使用相同的高度多元化的定量免疫荧光平台 结合严格的体视学设计分析AD患者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)和确定(CDR 3)痴呆患者。 我们将详细描述正常衰老时新皮质神经元亚群的蛋白质表达谱 并通过对人脑和阿尔茨海默病的进展在同一组织切片上成像大量的生物标志物， 能够逐个单元地对单元类型和状态进行分类。数据驱动的机器学习技术 将被应用于根据分子表型分配神经元亚类。我们将分析9/46区域 (LPFC)，它在AD中受到影响，以及17(V1)，它在AD中通常是备用的，复制实验 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，在层水平的分辨率。我们希望发现潜在的诊断和治疗方法 最终可能为早期疾病检测和预防提供新方法的目标 阿尔茨海默病关键神经元的进行性丧失。本副刊及其母项目将产生新颖和关键的 关于老年灵长类认知能力下降的神经基础的信息，并提供对特定情况的洞察 保护性抗炎抗氧化剂在正常和病理性脑老化中的作用机制。

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.