Cellular and circuit mechanisms underlying APOE-4 effects on olfaction.

项目概要： 了解危险因素和早期症状之间的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影响嗅觉的病理生理机制仍然存在 不清楚我们推测APOE-4失调导致神经回路兴奋-抑制失衡 AD早期嗅前核（anterior olfactory nucleus，AON）神经活动亢进导致OD 以下证据。首先，标志性AD病理出现在AON的Braak 0和I期 疾病的严重性，并随着AD的严重程度而增加。APOE-4升高AD发病机制。二、AD的严重程度 AON中的病理学（尤其是tau过度磷酸化）与APOE-4的拷贝数线性相关 等位基因第三，AON与嗅球、梨状皮质、海马、杏仁核， 和外侧内嗅皮质。所有这些嗅觉中枢在早期表现出易受AD发病的影响。 人APOE-4基因型转基因动物中的神经元过度兴奋。 根据我们的初步数据，以及AON与所有其他嗅觉脑中心的大量互连， 通过对APOE-4的有害作用特别敏感的神经递质传递，我们 推测APOE-4引起AON兴奋-抑制失衡和相关神经元功能障碍， 导致吸毒过量的电路提出了三个具体目标来检验我们的中心假设。目标1：确定 APOE-4对嗅觉依赖行为的影响目的2：研究APOE-4对AON神经元的作用 兴奋性目的3：研究APOE-4对AON突触过程的影响。拟议的工作是 旨在填补我们对APOE-4之间机制关系的知识空白， LOAD的遗传风险因素，以及细胞、电路和行为水平的OD。我们的发现可能会 阐明了在APOE-4中开发早期和准确诊断AD的有效策略， 甚至更广泛的人口。由于AD逐渐损害患者的认知和其他精神 因此，几年到几十年的能力大大损害了老年人的生活质量， 在美国和世界范围内，这种神经变性的早期和准确诊断将显著有益于 在医疗、经济、情感和社会层面上，

PROJECT SUMMARY: Understanding the relationship between risk factors and early symptoms is crucial to early and differential diagnosis of Alzheimer’s disease (AD). Expression of the ϵ-4 allele of human apolipoprotein E (APOE-4) 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 APOE-4 gene evince OD symptoms before AD pathogenesis, indicating a role of APOE-4 in functional disorders of the olfactory system. However, the pathophysiological mechanisms underlying the APOE-4 effects on olfaction remain unclear. We hypothesize that APOE-4 dysregulates neural circuits leading to excitation-inhibition imbalance and neural hyperactivity in the anterior olfactory nucleus (AON) to cause OD at the early stage of AD based on the following evidence. First, the hallmark AD pathologies appear in the AON in the Braak stages 0 and I of the disease and increase with AD severity. APOE-4 elevates AD pathogenesis. Second, the severity of AD pathology (especially tau hyperphosphorylation) in the AON correlates linearly with the copies of APOE-4 allele. Third, AON has direct interconnections with the olfactory bulb, piriform cortex, hippocampus, amygdala, and lateral entorhinal cortex. All these olfactory centers exhibit vulnerability to AD pathogenesis at early stages in humans and neuronal hyperexcitability in transgenic animals with humanized APOE-4 genotype. Based on our preliminary data and the massive interconnections of AON with all other olfactory brain centers via glutamatergic transmission that is particularly susceptible to detrimental effects of APOE-4, we hypothesize that APOE-4 causes excitation-inhibition imbalance in the AON and dysfunction of related neural circuits leading to OD. Three specific aims are proposed to test our central hypothesis. Aim 1: Determine APOE-4 impact on olfaction-dependent behaviors. Aim 2: Investigate APOE-4 effects on AON neuronal excitability. Aim 3: Characterize APOE-4 influence on synaptic processing in the AON. The proposed work is designed to fill gaps in our knowledge on the mechanistic relationship between APOE-4, a well-established genetic risk factor of LOAD, and OD at the cellular, circuit, and behavioral levels. Our findings will potentially shed light on development of effective strategies for early and accurate diagnosis of AD in the APOE-4- 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.