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: 10818843
• 负责人: Shaolin Liu
• 金额: $ 45.02万
• 依托单位: UNIVERSITY OF GEORGIA
• 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 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818843
• 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; Genetic; 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; behavior test; design; disease prognosis; genetic risk factor; improved; in vivo; 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; presynaptic; 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.

项目摘要： 了解风险因素和早期症状之间的因果关系对于早期和差异至关重要 诊断阿尔茨海默氏病（AD）。人载脂蛋白E（APOE4）基因的-4等位基因的表达， 发作后期发作的强大遗传危险因素，与 最早的广告症状 - 人类中的嗅觉防御（OD）。表达人ApoE4基因的动物 AD发病机理前的OD症状，表明APOE4在嗅觉的功能障碍中的作用 系统。但是，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破坏了星形胶质细胞神经元的相互作用，导致刺激性抑制 嗅球（OB）中的不平衡和突触功能障碍在基于AD的早期引起OD 以下证据。首先，在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，在这个年龄段的APOE4小鼠中气味敏感性降低。 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中的形态和物理缺陷。第三，作为钥匙 部分突触的元素，星形胶质细胞在突触中的神经递质吸收中起关键作用 裂口。我们的初步证据表明兴奋性和抑制性突触的上调 APOE4小鼠的主要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，我们观察到的醒目APOE4小鼠的二尖瓣细胞层的神经元超活活， 支持OB导致OD的兴奋性抑制不平衡。提出了三个特定目标来测试 我们的中心假设。目标1：确定APOE4的影响或调节星形胶质功能对气味 检测/灵敏度。 AIM 2：表征OB神经元活性和APOE4效应的星形胶质细胞调节。 AIM 3：研究OB中突触传递和APOE4效应的星形细胞调节。提议 蜂窝，电路和行为水平的工作旨在填补我们对星形细胞的知识的空白 OB中嗅觉信号的突触处理及其在APOE4相关OD中的作用的调节。 我们的发现可能会阐明为早期和准确诊断的有效策略的制定 APOE4携带甚至更广泛的人群中的AD。由于广告逐渐损害了患者的认知 数十年来的其他精神能力因此，显着损害了高年级的生活质量 美国和全球的人群，这种神经变性的早期和准确的诊断将显着 在医疗，经济，情感和社会水平上受益的人群及其社会。