Modulation of Olfactory Sensory Function by Amyloid-beta

β 淀粉样蛋白对嗅觉感觉功能的调节

基本信息

批准号：
8840862
负责人：
EFRAT LEVY
金额：
$ 31.42万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840862
关键词：
Affect Alzheimer&apos s Disease American Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Anatomy Area Behavior Behavioral Binding Biological Assay Cause of Death Cerebrum Characteristics Chronic Clinical Research Confusion Cysteine Proteinase Inhibitors Data Deposition Detection Diagnosis Discrimination Disease Early Diagnosis Etiology Excision Exhibits Family Foundations Functional disorder Genetic Models Healthcare Systems Human Knock-out Knockout Mice Learning Life Link Measurement Memory Memory Loss Methods Molecular Mus Mutation Odors Olfactory Pathways Pathogenesis Pathology Pattern Perception Physiological Process Protease Inhibitor Protein Precursors Rodent Rodent Model Role Sensory Sensory Physiology Sensory Process Smell Perception Staging Testing Transgenic Mice Transgenic Organisms United States Work base improved information processing insight motor impairment mutant neurophysiology neuropsychological novel overexpression post gamma-globulins prevent relating to nervous system remediation research study response spatiotemporal stefin

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the sixth leading cause of death in the United States, currently affects over 5 million North Americans and their families as well as the United States health care system. Impaired olfactory perceptual acuity, including deficits in odor identification, detection and discrimination are often observed early in the progression of AD. Understanding the neural basis for these sensory deficits is important in that 1) their etiology may unveil new insights into AD pathogenesis and 2) olfactory screens may serve as early-indicators of AD when combined with neuropsychological examinations. SPECIFIC AIMS: This proposal describes an experimental strategy aimed at understanding the contributions of amyloid-2 (A2) to olfactory system dysfunction. Behavioral, neurophysiological and molecular experiments will be performed in mice which overexpress human mutations of Amyloid 2 Precursor Protein (APP). Aim 1 will test the hypothesis that progressive A2 burden and AD-like olfactory perceptual deficits are related to abnormal odor information processing at local and global levels in AP transgenic mice. The remaining two aims will utilize novel genetic models of A2 remediation to examine methods to rescue/preserve olfactory function in APP transgenics. AIM 2 wil test the hypothesis that chronic enhancement of A2 degradation improves olfactory processing and perception by using mice which lack the protease inhibitor cystatin B (CBKO). AIM 3 will use mice over expressing the protease inhibitor cystatin C (CysC) to test the hypothesis that preventing A2 aggregation improves olfactory procesing and perception. These ongoing studies are the first to directly assess the contributions of A2 to olfactory perceptual dysfunction.

描述（由申请人提供）：美国第六大死亡原因阿尔茨海默氏病（AD）目前影响超过500万北美人及其家人以及美国的卫生保健系统。嗅觉感知性敏锐度受损，包括气味鉴定缺陷，检测和歧视，在AD的进展中经常观察到。了解这些感觉缺陷的神经基础很重要，因为1）他们的病因可能会揭示出对AD发病机理的新见解，而2）当与神经心理学检查结合使用时，嗅觉筛选可能是AD的早期调查者。具体目的：该提案描述了一种实验策略，旨在了解淀粉样蛋白-2（A2）对嗅觉系统功能障碍的贡献。在过表达淀粉样蛋白2前体蛋白（APP）的人类突变的小鼠中，将进行行为，神经生理和分子实验。 AIM 1将检验以下假设：渐进的A2负担和类似AD的嗅觉缺陷与AP转基因小鼠的局部和全球水平的异常气味信息处理有关。其余的两个目标将利用A2补救的新型遗传模型来检查APP转基因中拯救/保留嗅觉功能的方法。 AIM 2 WIL检验了以下假设：通过使用缺乏蛋白酶抑制剂Cystatin B（CBKO）的小鼠，A2降解的慢性增强可以改善嗅觉加工和感知。 AIM 3将使用小鼠表达蛋白酶抑制剂Cystatin C（CYSC）来检验以下假设，即防止A2聚集可以改善嗅觉的嗅觉和感知。这些正在进行的研究是第一个直接评估A2对嗅觉感知功能障碍的贡献的研究。