Brain abnormalities in transgenic mice

转基因小鼠的大脑异常

• 批准号: 6578723
• 负责人: DONALD L PRICE
• 金额: $ 15.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6578723
• 关键词: Alzheimer's disease; aging; amyloid proteins; behavior test; brain mapping; cell death; cognition; disease /disorder model; gene expression; genetically modified animals; glia; histopathology; laboratory mouse; memory; nerve /myelin protein; neuroanatomy; neurochemistry; neurons; neuropil; pathologic process

DESCRIPTION: (Adapted from the application) One of the major goals of our ADRC is to understand the biological substrates of mutant genes associated with impairments of cognition and memory. Project 2 takes advantage of the availability of several independent lines of mice (El-2 and C3-3) expressing a chimeric Mo/Hu-APP-695 polypeptide that harbors the Swedish double mutation (KM 570-571 NL). These mice express the mutant APP (Mo/Hu-APPswe) at levels approximately threefold greater than endogenous mouse APP and, between 20 and 24 months of age, develop AB42-immunoreactive deposits and associated cellular abnormalities. The investigators have controlled for the homogeneity of genetic background by back-crossing our transgene array into C57BL/6J mice for ten generations to obtain mice that are 99.99% congenic. Because their preliminary behavioral studies of Mo/Hu-APPswe Tg mice have documented the presence of mild memory deficits that antedate AB deposition, they hypothesize that shifts in levels of AB species, which occur significantly before AB deposition, are accompanied by subtle structural alterations in the neuropil (synaptic terminals/neurites) and that these lesions impact on behavioral performance. After the performance of these Tg mice is assessed in tasks of cognition/memory, animals will be sacrificed, and tissues will be analyzed for regional changes in biochemical markers (e.g., levels of AB peptide species, synaptic proteins, neurotransmitters and their enzymes) and the character/severity of the cellular pathology (e.g., abnormalities in synapses, AB deposition, reductions in synapses, loss of subsets of neurons, evidence of cell death, activation of glial cells, etc.) in specific regions of brain. They believe that these clinical-neurochemical-pathological correlations will help to define the biological substrates of impairments in these mice, and this information will provide important insight into similar processes that occur in elderly humans, particularly in the preclinical and early stages of disease.

描述：（改编自应用程序） 我们ADRC的主要目标之一是了解生物基质 与认知和记忆障碍有关的突变基因。项目 2利用了几个独立的小鼠品系的可用性 (El-2和C3-3）表达嵌合Mo/Hu-APP-695多肽，所述多肽含有 瑞典双突变（KM 570-571 NL）。这些老鼠表达了突变体 APP（Mo/Hu-APPswe）水平约为内源性的三倍 小鼠APP，并且在20至24个月龄之间，产生AB 42免疫反应性 沉积物和相关的细胞异常。调查人员已 控制遗传背景的同质性，通过回交我们的 转基因阵列到C57 BL/6 J小鼠中十代，以获得 99.99%同源。因为他们对Mo/Hu-APPswe的初步行为研究 Tg小鼠记录了AB之前存在的轻度记忆缺陷。 沉积，他们假设AB物种水平的变化， 在AB沉积之前，伴随着微妙的构造 神经元（突触末端/神经突）的改变，这些 病变对行为表现的影响。在这些Tg的性能之后， 评估小鼠的认知/记忆任务，将处死动物，并且 将分析组织的生化标记的区域变化（例如， AB肽种类、突触蛋白、神经递质及其 酶）和细胞病理学的特征/严重性（例如， 突触异常，AB沉积，突触减少， 神经元的子集、细胞死亡的证据、神经胶质细胞的激活等） 在大脑的特定区域。他们认为这些 临床-神经化学-病理相关性将有助于确定 这些小鼠中损伤的生物基质，这些信息将 为老年人的类似过程提供了重要的见解， 特别是在疾病的临床前和早期阶段。