APPPS1转基因阿尔兹海默病小鼠模型

APP基因位于染色体21q11.2-22.2上，由18个外显子和17个内含子组成。基因产物为跨膜糖蛋白，由APP基因通过选择性剪切翻译而成。APP至少有六种剪接形式，长度分别为365、563、695、714、751、770个氨基酸残基，其中695、751和770为主要形式。APP695主要在大脑表达，尤其在AD病人的海马回和皮层中APP695与APP751的比率异常，且与脑中这些部位斑块的数量呈正相关。由APP编码的APP蛋白经过加工水解可产生β淀粉样蛋白（β amyloid， Aβ）。病理情况下，APP经过β分泌酶和γ分泌酶分解生成Aβ40和Aβ42，其中Aβ42与AD患者脑中Aβ沉积和神经元的变性密切相关。在家族性AD患者中已鉴定出多个APP基因的突变位点。其中大部分突变位于外显子16和17的分泌酶裂解位点或APP跨膜区，如APP瑞典突变（APPswe：APP K670N和M671L）和伦敦突变（APPlon：APPV717I）。APP突变可改变APP的加工过程，导致具有神经毒性作用的Aβ42产生，引发多种病理机制，促使神经细胞凋亡或死亡，最终导致AD的发生。
PS1基因位于14号染色体，共10个外显子。PS1基因编码的PS蛋白为γ分泌酶的重要组成部分，在生成Aβ的过程中起重要作用。PS1突变是引起家族性AD的主要原因之一。PS1突变使其编码的蛋白亲水性环状结构域缺失，导致其构象改变，可影响γ-分泌酶的活性，使Aβ42生成增多。

The APP gene is located on chromosome 21q11.2-22.2, and consists of 18 exons and 17 introns. Its gene product is a transmembrane glycoprotein synthesized via alternative splicing of the APP gene precursor mRNA and subsequent translation. There are at least six splicing isoforms of APP, with lengths of 365, 563, 695, 714, 751 and 770 amino acid residues respectively, among which 695, 751 and 770 are the major isoforms. APP695 is predominantly expressed in the brain. Notably, the ratio of APP695 to APP751 is abnormal in the hippocampus and cerebral cortex of Alzheimer's disease (AD) patients, and is positively correlated with the number of amyloid plaques in these brain regions. The APP protein encoded by the APP gene can be processed and hydrolyzed to produce beta-amyloid (Aβ). Under pathological conditions, APP is degraded by β-secretase and γ-secretase to generate Aβ40 and Aβ42, among which Aβ42 is closely associated with Aβ deposition and neuronal degeneration in the brains of AD patients. Multiple mutational sites of the APP gene have been identified in patients with familial AD. Most of these mutations are located at the secretase cleavage sites of exons 16 and 17 or the transmembrane domain of APP, such as the APP Swedish mutation (APPswe: APP K670N and M671L) and the APP London mutation (APPlon: APP V717I). APP mutations can alter the processing of APP, leading to the production of neurotoxic Aβ42, triggering multiple pathological mechanisms, promoting neuronal apoptosis or death, and ultimately contributing to the onset of AD.

The PS1 gene is located on chromosome 14 and contains 10 exons. The presenilin (PS) protein encoded by the PS1 gene is a critical component of the γ-secretase complex, and plays an important role in the process of Aβ production. PS1 mutations are one of the main causes of familial AD. PS1 mutations result in the deletion of the hydrophilic loop domain of the encoded protein, leading to conformational changes that affect the activity of γ-secretase and increase the production of Aβ42.

搜集汇总

背景与挑战

背景概述

该数据集是一个APPPS1转基因阿尔兹海默病小鼠模型资源，属于国家人类疾病动物模型资源库，用于基础医学和神经性疾病研究。它通过转基因技术模拟阿尔兹海默病的病理机制，重点关注APP和PS1基因突变导致的β淀粉样蛋白生成和神经毒性作用，适用于AD相关实验研究。资源采用有条件共享方式，可通过线上申请获取。