APOE4 effects on glia-neuron interaction in the olfactory bulb

项目总结： 了解风险因素和早期症状之间的因果关系对于早期和鉴别至关重要。 阿尔茨海默病(AD)的诊断。人载脂蛋白E基因-4等位基因的表达 发作性迟发性阿尔茨海默病发病的最强遗传风险因素与 人类最早的AD症状-嗅觉缺陷(OD)。表达人类载脂蛋白4基因的动物表明 AD发病前的OD症状，提示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干扰星形胶质细胞-神经元的相互作用，导致兴奋-抑制 阿尔茨海默病早期嗅球失衡和突触功能障碍与OD的关系 以下是证据。首先，早在APOE4小鼠的OB中就观察到了网络功能障碍 六个月大。我们的初步数据一直显示，APOE4小鼠在这个年龄段对气味的敏感度降低。 其次，载脂蛋白E主要由OB肾小球周围的星形胶质细胞表达。我们的初步研究 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 作为部分突触的一部分，星形胶质细胞在从突触吸收神经递质方面发挥着关键作用 克利夫茨。我们的初步证据显示兴奋性突触和抑制性突触均上调 APOE4小鼠主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APOE4小鼠二尖瓣细胞层的神经元过度活动， 支持OB的兴奋-抑制失衡，导致OD。提出了三个具体的测试目标 我们的核心假设。目的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。目的2：研究星形胶质细胞对OB神经元活动的调控和APOE4的影响。 目的3：探讨星形细胞对OB区突触传递的调控及APOE4的作用。建议数 在细胞、电路和行为层面的工作旨在填补我们在星形细胞方面的知识空白 嗅觉信号突触处理的调制及其在APOE4相关OD中的作用。 我们的发现可能会为开发有效的早期和准确诊断策略提供帮助。 在载脂蛋白4携带者甚至更广泛的人群中，AD的风险更大。阿尔茨海默病患者认知功能进行性损害 和其他几年到几十年的心智能力，从而显著影响老年人的生活质量 在美国和世界各地的人群中，这种神经变性的早期和准确诊断将显著 使受影响人口及其社会在医疗、经济、情感和社会层面受益。

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.