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

项目总结： 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)。表达人载脂蛋白E-4基因的动物 AD发病前的OD症状，提示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。我们假设APOE-4导致神经回路失调，导致兴奋-抑制失衡 和前嗅核(AON)的神经过度活动在AD的早期引起OD 根据以下证据。首先，标志性的AD病理出现在Braak阶段0和I的Aon中 并随着AD严重程度的增加而增加。APOE-4促进AD发病。第二，阿尔茨海默病的严重性 AON的病理改变(尤其是tau蛋白过度磷酸化)与APOE-4的拷贝数呈线性相关 等位基因。第三，全能神经与嗅球、梨状皮质、海马体、杏仁核、 和外侧内嗅皮层。所有这些嗅觉中枢在早期都表现出对AD发病的易感性 人类分期和人源化apoe-4基因转基因动物的神经元过度兴奋性。 根据我们的初步数据和Aon与所有其他嗅觉大脑中心的大量相互联系 通过谷氨酸能传递，特别容易受到载脂蛋白-4的有害影响，我们 APOE-4导致AON兴奋-抑制失衡及相关神经功能障碍的假说 通向吸食过量的电路。为了检验我们的中心假设，我们提出了三个具体目标。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神经元的影响 兴奋性。目的3：研究APOE-4对AON突触加工的影响。建议的工作是 旨在填补我们在APOE-4之间的机械关系的知识空白，一个公认的 细胞、回路和行为水平上的负荷和OD的遗传危险因素。我们的发现可能会 为早期和准确诊断APOE-4中AD的有效策略的制定提供了帮助 携带着甚至更广泛的人口。由于AD会逐渐损害患者的认知和其他精神 因此，持续数年到数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极大地受益于 在医疗、经济、情感和社会层面上受影响的人口及其社会。

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.