APOE4 effects on glia-neuron interaction in the olfactory bulb

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。人载脂蛋白E（APOE 4）基因的α-4等位基因的表达， 最强的遗传风险因素的发展，阵发性晚发性AD，密切相关， 人类最早的AD症状-嗅觉缺陷（OD）。表达人APOE 4基因的动物显示， AD发病前的OD症状，表明APOE 4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APOE 4破坏星形胶质细胞-神经元相互作用，导致兴奋-抑制 基于AD早期阶段，嗅球（OB）的失衡和突触功能障碍导致OD 以下证据。首先，在APOE 4小鼠的OB中观察到网络功能障碍， 六个月大一致地，我们的初步数据显示在这个年龄APOE 4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 揭示了APOE 4小鼠肾小球星形胶质细胞的形态和生理缺陷。第三，作为一把钥匙 星形胶质细胞是分裂突触的组成部分，在从突触摄取神经递质中起关键作用。 裂缝我们的初步证据表明，兴奋性和抑制性突触的上调， APOE 4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，我们观察到清醒的APOE 4小鼠的二尖瓣细胞层中的神经元过度活动， 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 我们的核心假设目的1：确定APOE 4或调节星形胶质细胞功能对气味的影响 检测/灵敏度。目的2：表征星形胶质细胞对OB神经元活动的调节和APOE 4作用。 目的3：研究星形胶质细胞对突触传递的调节和APOE 4在OB中的作用。拟议 在细胞、电路和行为水平上的工作旨在填补我们对星形胶质细胞的知识空白， OB中嗅觉信号突触处理的调节及其在APOE 4相关OD中的作用。 我们的研究结果将可能为早期和准确诊断的有效策略的发展提供线索 在携带APOE 4甚至更广泛的人群中的AD。由于AD逐渐损害患者的认知能力， 和其他精神能力，从而大大损害了老年人的生活质量。 在美国和世界范围内的人群中，这种神经变性的早期和准确诊断将显着 在医疗、经济、情感和社会层面上造福于受影响的人口及其社会。

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.