APP Metabolism in Transgenic Down Syndrome Mouse Models

转基因唐氏综合症小鼠模型中的 APP 代谢

• 批准号: 7624245
• 负责人: Jennifer Choi Tudor
• 金额: $ 4.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624245
• 关键词: Abeta synthesis; Affect; Age; Aging; Alzheimer' s Disease; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Brain; C-terminal; Cell Fractionation; Cells; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 21; Cleaved cell; Diploidy; Down Syndrome; Early Endosome; Endocytosis; Gene Dosage; Genes; Human; Human Chromosomes; Incidence; Individual; Laboratories; Life; Link; Measures; Metabolism; Modality; Modeling; Monoclonal Antibodies; Mus; Nerve Degeneration; Neurons; Pathogenesis; Pathology; Pathway interactions; Peptides; Production; Protein Fragment; Proteins; Proteolytic Processing; Senile Plaques; Techniques; Testing; Transgenic Organisms; Vaccination; age related; aged; aging brain; amyloid precursor protein processing; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; in vivo; juvenile animal; mouse Ts65Dn; mouse model; novel; protein metabolism; protein metabolite

DESCRIPTION (provided by applicant): Accumulation of the small A beta peptide in the brain in beta-amyloid plaques is an invariant feature of Alzheimer's disease (AD), the most common type of neurodegeneration affecting over six million Americans. Abeta is derived from the amyloid precursor protein by proteolytic processing of the amyloid precursor protein (APP). Individuals with Down syndrome (DS; trisomy 21) inevitably develop AD pathology, including beta-amyloid plaques, in their fourth or fifth decade of life. The App gene is located on human chromosome 21, and it is generally thought that this additional gene copy of App mechanistically leads to AD in DS individuals. Using mouse models of human DS such as the Ts65Dn mouse, which is trisomic for a segment of murine chromosome 16 orthologous to the DS critical region of human chromosome 21, the metabolism of APP and the production of Abeta will be examined in the intact CNS. APP metabolite levels will be determined as a function of aging in the Ts65Dn mouse, and alterations in the rate of APP and APP metabolite (secretory APP fragments, C-terminal APP fragments, Abeta) turnover in vivo in the Ts65Dn mouse will be examined (Aim 1). The Ts65Dn mouse also shows abnormalities in endocytosis seen selectively in AD and DS and age-dependent basal forebrain cholinergic neuron degeneration. Given that it has been previously shown that APP proteolytic processing can occur in early endosomes, the link between neuronal endocytosis alterations in the Ts65Dn model and APP metabolism will be examined using immunolocalization techniques as well as subcellular fractionation (Aim 2). The hypothesis that APP mismetabolism in the Ts65Dn mouse is mechanistically linked to neurodegeneration will be tested by reducing Abeta levels in the CNS using passive vaccination with an anti-murine Abeta monoclonal antibody (Aim 3), thereby establishing a connection between neurodegeneration and Abeta levels/APP mismetabolism in this model. These studies will characterize in vivo brain APP metabolism and test the idea that APP mismetabolism is a cause of basal forebrain cholinergic neurodegeneration in a DS model. These findings will have important implication for the mechanisms of AD pathogenesis in DS and may suggest common modalities of neurodegeneration with AD.

描述（由申请人提供）：在β-淀粉样蛋白斑块中，小型Aβ肽在大脑中的积累是阿尔茨海默氏病（AD）的一个不变特征，这是影响超过600万美国人的最常见的神经变性类型。 Abeta通过淀粉样蛋白前体蛋白（APP）的蛋白水解加工源自淀粉样蛋白前体蛋白。患有唐氏综合症的个体（DS;三体术21）不可避免地会在生命的第四或第五个十年中发展出包括β-淀粉样蛋白斑块在内的AD病理学。该应用基因位于人类染色体21上，通常认为该APP的额外基因副本在DS个体中会导致AD。使用人类DS的小鼠模型，例如TS65DN小鼠，该小鼠是三体染色体16染色体与人类染色体染色体染色体临界区域的三段，APP的代谢和ABETA的产生，将在完整的CNS中检查。 APP代谢物水平将根据TS65DN鼠标的老化确定，并且将检查TS65DN鼠标的APP和APP代谢物（分泌App片段，C端App片段，ABETA）周转率的变化（AIM 1）。 TS65DN小鼠还显示出在AD和DS中选择性观察到的内吞作用异常以及年龄依赖性的基础前脑胆碱能神经元变性。鉴于以前已经证明，早期内体可能会发生APP蛋白水解处理，因此将使用免疫定位技术以及亚细胞分离的TS65DN模型中的神经元内吞作用改变与APP代谢之间的联系（AIM 2）。 TS65DN鼠标中的APP不匹配代谢与神经退行性相关的假说将通过使用无源疫苗接种使用抗毛碱ABETA单克隆抗体进行测试来测试中枢神经系统中的Abeta水平（AIM 3），从而在神经变性级别之间建立了与Abletageneration级别之间的联系。这些研究将表征体内脑应用代谢的代谢，并测试App不匹配代谢是在DS模型中基础前脑胆碱能神经变性的原因。这些发现将对DS中AD发病机理的机制具有重要意义，并可能暗示神经退行性的常见方式使用AD。