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 人类载脂蛋白 E (APOE-4) 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 APOE-4 基因的动物。 AD 发病之前出现 OD 症状，表明 APOE-4 在嗅觉功能障碍中的作用 然而，APOE-4 对嗅觉影响的病理生理机制仍然存在。 我们研究发现 APOE-4 调节神经回路导致兴奋抑制失衡。 AD 早期阶段，前嗅核 (AON) 神经过度活跃导致 OD 首先，标志性 AD 病理出现在 Braak 0 期和 I 期的 AON 中。 APOE-4 会随着 AD 的严重程度而升高。 其次，AD 的严重程度。 AON 中的病理学（尤其是 tau 过度磷酸化）与 APOE-4 的拷贝呈线性相关 第三，AON 与嗅球、梨状皮层、海马体、杏仁核有直接联系。 所有这些嗅觉中心在 AD 发病早期都表现出脆弱性。 人类的阶段和具有人源化 APOE-4 基因型的转基因动物的神经过度兴奋。 基于我们的初步数据以及 AON 与所有其他嗅觉大脑中心的大规模互连 通过谷氨酸能传输特别容易受到 APOE-4 的有害影响，我们 敏锐地发现 APOE-4 会导致 AON 兴奋抑制失衡以及相关神经功能障碍 提出了三个具体目标来检验我们的中心假设：确定。 APOE-4 对嗅觉依赖性行为的影响 目标 2：研究 APOE-4 对 AON 神经元的影响。 目标 3：表征 APOE-4 对 AON 突触处理的影响。 旨在填补我们对 APOE-4 之间机械关系的知识空白，APOE-4 是一种成熟的 我们的研究结果可能会在细胞、回路和行为水平上影响 LOAD 和 OD 的遗传风险因素。 阐明了 APOE-4- 中早期准确诊断 AD 的有效策略的制定 由于 AD 逐渐损害患者的认知和其他精神。 多年来的能力，从而严重损害了老年人口的生活质量 在美国和世界范围内，对这种神经退行性疾病的早期准确诊断将极大地有益于 在医疗、经济、情感和社会层面受影响的人群及其社会。