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）：阿尔茨海默病（AD）是美国第六大死因，目前影响着超过 500 万北美人及其家人以及美国医疗保健系统。在 AD 进展的早期，经常会观察到嗅觉敏锐度受损，包括气味识别、检测和辨别能力的缺陷。了解这些感觉缺陷的神经基础非常重要，因为 1) 它们的病因学可能揭示 AD 发病机制的新见解，2) 与神经心理学检查相结合时，嗅觉屏幕可能作为 AD 的早期指标。具体目标：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影响。行为、神经生理学和分子实验将在过度表达人类淀粉样蛋白 2 前体蛋白 (APP) 突变的小鼠中进行。目标 1 将检验以下假设：渐进性 A2 负担和 AD 样嗅觉感知缺陷与 AP 转基因小鼠局部和整体水平的异常气味信息处理有关。剩下的两个目标将利用 A2 修复的新型遗传模型来研究在 APP 转基因中拯救/保留嗅觉功能的方法。 AIM 2 将通过使用缺乏蛋白酶抑制剂胱抑素 B (CBKO) 的小鼠来测试 A2 降解的长期增强可改善嗅觉处理和感知的假设。 AIM 3 将使用过度表达蛋白酶抑制剂半胱氨酸蛋白酶抑制剂 C (CysC) 的小鼠来测试防止 A2 聚集改善嗅觉处理和感知的假设。这些正在进行的研究首次直接评估 A2 对嗅觉知觉功能障碍的影响。