APOE4 effects on glia-neuron interaction in the olfactory bulb

APOE4 对嗅球神经胶质细胞相互作用的影响

• 批准号: 10440056
• 负责人: Shaolin Liu
• 金额: $ 46.99万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440056
• 关键词: Acceleration; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Animal Model; Animals; Apolipoprotein E; Astrocytes; Atrophic; Behavioral; Blood - brain barrier anatomy; Blood Vessels; Brain; Clinical; Clinical Research; Cognitive; Complex; Data; Dementia; Dendrodendritic Synapse; Detection; Development; Differential Diagnosis; Disease; Disease Progression; Early Diagnosis; Electrophysiology (science); Elements; Emotional; Encapsulated; Energy Metabolism; Energy Supply; Ethics; Etiology; Extracellular Space; Functional disorder; Genes; Genotype; Human; Hyperactivity; Impairment; In Vitro; Incidence; Interneurons; Knowledge; Late Onset Alzheimer Disease; Light; Lipoproteins; Medical; Morphology; Mus; Nerve Degeneration; Neurobiology; Neuroglia; Neurons; Odors; Olfactory Cortex; Olfactory Pathways; Output; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Physiological; Pilot Projects; Play; Population; Positioning Attribute; Process; Progressive Disease; Proteins; Psyche structure; Quality of life; Research; Risk Factors; Role; Signal Transduction; Smell Perception; Societies; Structure; Symptoms; Synapses; Synaptic Cleft; Synaptic Transmission; Testing; Up-Regulation; Vascular blood supply; Work; accurate diagnosis; apolipoprotein E-4; awake; base; behavior test; design; detection sensitivity; disease prognosis; genetic risk factor; improved; in vivo; lipid metabolism; mitral cell; nervous system disorder; network dysfunction; neuronal excitability; neurotransmitter uptake; new technology; novel strategies; olfactory bulb; olfactory bulb glomeruli; postsynaptic; potassium ion; pre-clinical; prodromal Alzheimer' s disease; prognosis biomarker; response; signal processing; social

PROJECT SUMMARY: Understanding the causality between risk factors and early symptoms is crucial to early and differential diagnosis of Alzheimer’s disease (AD). Expression of the -4 allele of human apolipoprotein E (APOE4) gene, the strongest genetic risk factor for development of the episodic late-onset AD, associates tightly with the earliest AD symptom - olfactory deficit (OD) in humans. Animals expressing the human APOE4 gene evince OD symptoms before AD pathogenesis, indicating a role of APOE4 in functional disorders of the olfactory system. However, the pathophysiological mechanisms underlying the APOE-4 actions on olfaction remain unclear. We hypothesize that APOE4 disrupts astrocyte-neuron interaction leading to excitation-inhibition imbalance and synaptic dysfunction in the olfactory bulb (OB) to cause OD at the early stage of AD based on the following evidence. First, network dysfunction has been observed in the OB of APOE4 mice as young as 6-month-old. Consistently, our preliminary data show reduced odor sensitivity in APOE4 mice at this age. Second, APOE is predominantly expressed by astrocytes surrounding each OB glomerulus. Our pilot studies reveal morphological and physiological deficits in the glomerular astrocytes in APOE4 mice. Third, as a key element of the partite synapses, astrocytes play pivotal roles in uptake of neurotransmitters from the synaptic clefts. Our preliminary evidence demonstrates upregulation of both excitatory and inhibitory synaptic responses in the principal OB output neurons of APOE4 mice, congruent with dysfunction of glomerular astrocytes. Finally, our observed neuronal hyperactivities in the mitral cell layer of awake APOE4 mice, supporting excitation-inhibition imbalance in the OB leading to OD. Three specific aims are proposed to test our central hypothesis. Aim 1: Determine effects of APOE4 or modulating astrocytic functions on odor detection/sensitivity. Aim 2: Characterize astrocytic modulation of OB neuronal activities and APOE4 effects. Aim 3: Investigate astrocytic modulation of synaptic transmission and APOE4 effects in the OB. The proposed work at the cellular, circuit, and behavioral levels is designed to fill gaps in our knowledge on astrocytic modulation of synaptic processing of olfactory signals in the OB and its roles in the APOE4-associated OD. Our findings will potentially shed light on development of effective strategies for early and accurate diagnosis of AD in the APOE4-carrying or even broader populations. Since AD progressively impairs patient’s cognitive and other mental abilities for years to decades thus significantly compromises the quality of life in the senior populations in the US and worldwide, early and accurate diagnosis of this neurodegeneration will significantly benefit the affected populations and their societies at the medical, economical, emotional, and social levels.

项目概要： 了解危险因素和早期症状之间的因果关系对于早期和鉴别诊断至关重要 阿尔茨海默病（AD）的诊断。人类载脂蛋白 E (APOE4) 基因的 -4 等位基因的表达， 发生阵发性迟发性 AD 的最强遗传风险因素，与 最早的AD症状——人类嗅觉缺陷（OD）。表达人类 APOE4 基因的动物 AD 发病之前出现 OD 症状，表明 APOE4 在嗅觉功能障碍中的作用 系统。然而，APOE-4 对嗅觉作用的病理生理机制仍然存在 不清楚。我们假设 APOE4 破坏星形胶质细胞-神经元相互作用，导致兴奋抑制 AD早期阶段嗅球（OB）失衡和突触功能障碍导致OD 以下证据。首先，在年幼的 APOE4 小鼠的 OB 中观察到网络功能障碍 6个月大。一致地，我们的初步数据显示该年龄的 APOE4 小鼠的气味敏感性降低。 其次，APOE 主要由每个 OB 肾小球周围的星形胶质细胞表达。我们的试点研究 揭示 APOE4 小鼠肾小球星形胶质细胞的形态和生理缺陷。三、作为钥匙 星形胶质细胞是部分突触的组成部分，在从突触摄取神经递质方面发挥着关键作用 裂缝。我们的初步证据表明兴奋性和抑制性突触均上调 APOE4 小鼠主要 OB 输出神经元的反应，与肾小球功能障碍一致 星形胶质细胞。最后，我们观察到清醒 APOE4 小鼠二尖瓣细胞层神经元过度活跃， 支持 OB 中的兴奋抑制失衡导致 OD。提出了三个具体目标来测试 我们的中心假设。目标 1：确定 APOE4 或调节星形胶质细胞功能对气味的影响 检测/灵敏度。目标 2：表征 OB 神经元活动的星形胶质细胞调节和 APOE4 效应。 目标 3：研究 OB 中突触传递的星形胶质细胞调节和 APOE4 效应。拟议的 在细胞、电路和行为层面的工作旨在填补我们在星形胶质细胞方面的知识空白 OB 中嗅觉信号突触处理的调节及其在 APOE4 相关 OD 中的作用。 我们的研究结果可能有助于制定有效的早期准确诊断策略 AD 在携带 APOE4 的人群中甚至更广泛的人群中都有发生。由于 AD 逐渐损害患者的认知能力 和其他心理能力长达数年至数十年，从而严重损害老年人的生活质量 对于美国和世界各地的人群来说，这种神经退行性疾病的早期和准确诊断将显着 在医疗、经济、情感和社会层面使受影响人群及其社会受益。