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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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&apos s disease prognosis biomarker response signal processing social

项目摘要

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然而，APOE-4 对嗅觉作用的病理生理机制仍然存在。我们研究发现 APOE4 会破坏星形胶质细胞与神经元的相互作用，从而导致兴奋抑制。 AD早期阶段嗅球（OB）失衡和突触功能障碍导致OD 首先，在年幼的 APOE4 小鼠的 OB 中观察到网络功能障碍。 6 个月大时，我们的初步数据一致显示 APOE4 小鼠在这个年龄段的气味敏感性降低。其次，APOE 主要由每个 OB 肾小球周围的星形胶质细胞表达。揭示 APOE4 小鼠肾小球星形胶质细胞的形态和生理缺陷第三，作为关键。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最后，我们观察到清醒 APOE4 小鼠二尖瓣细胞层的神经元过度活跃，支持 OB 中的兴奋抑制失衡导致 OD，提出了三个具体目标进行测试。我们的中心假设 1：确定 APOE4 或调节星形胶质细胞功能对气味的影响。目标 2：表征 OB 神经活动和 APOE4 效应的星形胶质细胞调节。目标 3：研究 OB 中突触传递的星形胶质细胞调节和 APOE4 效应。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 携带 APOE4 的人群甚至更广泛的人群，因为 AD 逐渐损害患者的认知能力。和其他心理能力数年至数十年的显着影响，从而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、情感和社会层面造福受影响人群及其社会。