NEUROFILAMENT MID-SIZED TRANSGENIC MOUSE AS A MODEL FOR ALZHEIMER'S DISEASE

神经丝中型转基因小鼠作为阿尔茨海默病模型

• 批准号: 5204479
• 负责人: VAHRAM HAROUTUNIAN
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5204479
• 关键词: Alzheimer's disease; acetylcholinesterase; avoidance behavior; behavior test; behavioral habituation /sensitization; choline acetyltransferase; cognition disorders; disease /disorder model; genetically modified animals; hippocampus; laboratory mouse; long term potentiation; longitudinal animal study; memory disorders; model design /development; neuritic plaques; neurochemistry; neurofibrillary tangles; neurofilament proteins; neuropeptides; neuropharmacology; pathologic process; physostigmine; scopolamine; voltage /patch clamp

Advances in the treatment and understanding of AD are hampered by the lack of appropriate animal model systems. None of the model systems studied have led to the development of any of the neuropathological hallmarks of AD, such as neuritic plaques and neurofibrillary tangles. The human neurofilament mid-sized transgenic mouse (NF-M) has been neuropathologically characterized and found to possess some of the pathological features of AD. Whether or not these animals represent a more adequate model of the cognitive deficits of AD than the models currently available remains to be determined. The goal of this project is to determine the degree to which the NF-M mouse models the cognitive and pharmacological features of AD relative to operationally defined criteria for an adequate animal model system. We will test the hypotheses that a) the NF-M transgene produces learning and memory deficits; b) these cognitive impairments follow a time course similar to the time course of development of neuropathologic lesions; c) the NF-M transgenic mice are hypersensitive to anticholinergic agents and hyposensitive to cholinomimetic agents; and d) the in vivo cognitive deficits are reflected in deficits in the hippocampal long term potentiation (LTP) model of learning and memory. Pilot studies have been conducted to determine the appropriate parameters and procedures for the proposed behavioral studies. The locomotor activity and open field behavior of non-transgenic mice have been studies and parameters for assessing short and long-term habituation have been established. Passive avoidance acquisition and retention parameters have been outlined in non-transgenic mice with and without cognitive deficits caused by lesions of the cholinergic forebrain. Animals transgenic for the human vasopressin gene have been behaviorally characterized and studied using a subset of the assessment procedures proposed for the study of NF-M mice. Finally, fifteen DBA/J2 female mice have been mated with 10 NF-M transgenic males and a mating schedule has been worked out to provide the requisite numbers of animals for the proposed studies. Longitudinal studies of learning and memory will begin within the next 4 weeks when the first of the NF-M transgenic litters are weaned.

缺乏的治疗和理解的进步受到了阻碍 适当的动物模型系统。 没有研究的模型系统 导致了任何神经病理学标志的发展 AD，例如神经斑块和神经原纤维缠结。 人类 神经丝中大型转基因小鼠（NF-M）已经 神经病理学的特征并发现有一些 AD的病理特征。 这些动物是否代表更多 与当前模型相比，AD的认知缺陷的适当模型 可用的尚待确定。 这个项目的目标是 确定NF-M小鼠对认知和 广告相对于操作定义标准的药理特征 适用于适当的动物模型系统。 我们将测试A） NF-M转基因会产生学习和记忆缺陷； b）这些 认知障碍遵循类似于时间课程的时间课程 神经病理病变的发展； c）NF-M转基因小鼠是 对抗胆碱能剂的高度敏感，对 胆碱成剂； d）体内认知缺陷被反映 在海马长期增强（LTP）模型的缺陷中 学习和记忆。 进行了试点研究以确定 提出的行为研究的适当参数和程序。 非转基因小鼠的运动活性和开放式行为具有 是评估短期和长期习惯的研究和参数 已建立。 被动避免获得和保留 参数已在没有和没有的非转基因小鼠中概述 由胆碱能的前脑病变引起的认知缺陷。 动物 人加压素基因的转基因在行为上已经是行为 使用评估程序的子集进行了表征和研究 提议研究NF-M小鼠。 最后，十五只DBA/J2雌鼠 已经与10 NF-M转基因男性交配，交配时间表已 已经制定了为提供必要数量的动物 拟议的研究。 学习和记忆的纵向研究将开始 在接下来的4周内，NF-M转基因垃圾是 断奶。