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

APOE-4 对嗅觉影响的细胞和电路机制。

• 批准号: 10812781
• 负责人: Shaolin Liu
• 金额: $ 151.64万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10812781
• 关键词: Cellular; circuit; mechanisms; underlying; APOE

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 -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.

项目摘要： 了解风险因素与早期症状之间的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（APOE-4）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ApoE-4基因的动物 AD发病机理前的OD症状，表明APOE-4在嗅觉的功能障碍中的作用 系统。但是，APOE-4对嗅觉影响的基础的病理生理机制仍然存在 不清楚。我们假设APOE-4失调神经回路导致兴奋性抑制失衡 前嗅觉核（AON）中的神经多动症在基于AD的早期阶段引起OD 关于以下证据。首先，Hallmark广告病理出现在Braak阶段的AON中，我 疾病的疾病并随着广告严重程度而增加。 APOE-4提高了AD发病机理。第二，广告的严重性 AON中的病理（尤其是Tau高磷酸化）与APOE-4的副本线性相关 等位基因。第三，AON与嗅球，梨状皮层，海马，杏仁核直接互连 和侧内皮层。所有这些嗅觉中心在早期表现出脆弱的AD发病机理 人性化动物中人性化动物的人类和神经元过度兴奋的阶段，具有人源化APOE-4基因型。 根据我们的初步数据和与所有其他嗅觉脑中心的AON的大量互连 通过特别容易受到APOE-4有害影响的谷氨酸能传播，我们 假设APOE-4会导致相关神经的AON和功能障碍引起兴奋性抑制失衡 电路导致OD。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对嗅觉依赖性行为的影响。 AIM 2：研究APOE-4对AON神经元的影响 兴奋性。 AIM 3：表征APOE-4对AON中突触处理的影响。拟议的工作是 旨在填补我们对APOE-4之间机械关系的知识的空白，这是一个公认的 负载的遗传危险因素，以及在细胞，电路和行为水平上的OD。我们的发现可能会 阐明了在APOE-4-中的早期和准确诊断的有效策略的制定 携带甚至更广泛的人口。由于广告逐渐损害了患者的认知和其他精神 因此，数十年来的能力严重损害了高级人口的生活质量 美国和全球，这种神经变性的早期和准确的诊断将显着受益 在医疗，经济，情感和社会水平上影响了人口及其社会。