Olfactory Epithelium Responses to Human APOE Alleles

项目总结： 嗅觉缺陷在几十年前就被认为是早期阿尔茨海默病患者的早期症状 疾病。然而，这些发现对研究、诊断和治疗的影响小于预期。 这种疾病。尽管中枢神经系统嗅觉通路受到斑块和/或缠结的影响，但 这些症状是晚期疾病的特征，并不会将嗅觉系统与其他疾病的病灶区分开来 阿尔茨海默氏症的研究。也许是因为嗅觉上皮的再生能力 掩盖了嗅觉感觉神经元对阿尔茨海默病的易感性，特别是早期事件 导致这种疾病的神经退行性变的特征，研究嗅觉上皮是如何 受阿尔茨海默氏症的影响，她陷入了痛苦之中。明确的证据表明，嗅觉感觉神经元 上皮细胞对导致或增加阿尔茨海默病风险的因素很敏感最近出现了， 然而。这些发现表明，嗅觉上皮是一个有价值的模型，可以用来研究危险因素如何影响 阿尔茨海默病会影响神经元及其支持细胞。到目前为止，这些数据与 大脑，证据表明嗅觉上皮可能是中枢神经系统活动的先导。 神经系统。嗅觉上皮活检评估疾病进展的可及性 个人和不能通过血脑屏障的药物进一步提高了 以嗅觉上皮为模型。这个项目调查阿尔茨海默氏症的一个关键危险因素的影响。 疾病，APOE基因，在嗅上皮细胞及其嗅觉神经元上。这些实验 重点识别早期事件及其对表型和功能的影响程度。它使用鼠标 疾病的模型，包括先前用于研究大脑影响的已建立的遗传模型 以及一种新的模型，允许随意从神经退行性基因型切换到神经保护型 基因分型。后者允许测试细胞和分子事件是否与易感性有关 阿尔茨海默氏症可以通过体内基因操作来预防或逆转，结果将告诉我们 并激励进一步的工作，以治愈这种疾病。

Project Summary: Deficits in olfaction were recognized decades ago as early symptoms in people with incipient Alzheimer’s Disease. However, these discoveries have had less impact than hoped on the study, diagnosis, and treatment of this disease. Though central nervous system olfactory pathways suffer the plaques and/or tangles that are characteristic of late-stage disease, these symptoms do not set the olfactory system apart from other foci of research into Alzheimer’s Disease. Perhaps because the regenerative capacity of the olfactory epithelium obscured the vulnerability of olfactory sensory neurons to Alzheimer’s Disease, especially the early events leading to the neurodegeneration characteristic of the disease, study of how the olfactory epithelium is impacted by Alzheimer’s Disease languished. Clear evidence that the olfactory sensory neurons in the epithelium are susceptible to factors that cause or increase risk of Alzheimer’s Disease has recently emerged, however. These findings demonstrate that the olfactory epithelium is a worthy model of how risk factors for Alzheimer’s Disease affect neurons and their supporting cells. Thus far the data correlate well with effects in the brain, evidence that the olfactory epithelium may be a bellwether for events transpiring in the central nervous system. The accessibility of the olfactory epithelium for biopsy to assess disease progression in individuals and to drugs that cannot pass the blood brain barrier further elevates the significance of the olfactory epithelium as a model. This project investigates the effects of a critical risk factor for Alzheimer’s Disease, APOE genotype, on the olfactory epithelium and its olfactory sensory neurons. The experiments focus on identifying early events and the strength of their effects on phenotype and function. It uses mouse models of the disease, including established genetic models previously used to investigate effects in the brain and a novel model that allows switching at will from a neurodegenerative genotype to a neuroprotective genotype. The latter allows testing of whether cellular and molecular events associated with vulnerability to Alzheimer’s Disease can be prevented or reversed by in vivo genetic manipulation, outcomes that would inform and inspire further work towards curing this disease.