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: 7480918
• 负责人: Jennifer Choi Tudor
• 金额: $ 4.1万
• 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 2010-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480918
• 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; Cholinergic Agents; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 21; Cleaved cell; Diploidy; Down Syndrome; Early Endosome; Endocytosis; Gene Dosage; Genes; Human; 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; Rate; Senile Plaques; Techniques; Testing; Thinking; 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）：小A β肽在大脑中β-淀粉样斑块中的积累是阿尔茨海默病（AD）的不变特征，AD是影响超过600万美国人的最常见类型的神经变性。Abeta通过淀粉样前体蛋白（APP）的蛋白水解加工衍生自淀粉样前体蛋白。患有唐氏综合征（DS; 21三体）的个体在其生命的第四或第五个十年中不可避免地发展AD病理，包括β-淀粉样蛋白斑块。App基因位于人类21号染色体上，通常认为App的这种额外基因拷贝在机制上导致DS个体中的AD。使用人DS的小鼠模型，如Ts 65 Dn小鼠（其为小鼠染色体16的一段三体，与人染色体21的DS关键区域正交），将在完整CNS中检查APP的代谢和Abeta的产生。APP代谢物水平将被确定为Ts 65 Dn小鼠中衰老的函数，并且将检查Ts 65 Dn小鼠中体内APP和APP代谢物（分泌型APP片段、C-末端APP片段、Abeta）周转率的改变（目的1）。Ts 65 Dn小鼠还显示出在AD和DS中选择性观察到的内吞异常以及年龄依赖性基底前脑胆碱能神经元变性。鉴于之前已经表明APP蛋白水解加工可以发生在早期内体中，将使用免疫定位技术以及亚细胞分级分离来检查Ts 65 Dn模型中神经元内吞作用改变与APP代谢之间的联系（目的2）。将通过使用抗鼠Abeta单克隆抗体被动接种降低CNS中的Abeta水平（Aim 3）来测试Ts 65 Dn小鼠中APP代谢异常与神经退行性变机械相关的假设，从而建立神经退行性变和Abeta之间的联系水平/APP代谢异常在该模型中。这些研究将表征体内脑APP代谢，并测试APP代谢不良是DS模型中基底前脑胆碱能神经变性的原因。这些发现对AD发病机制的研究具有重要意义，并可能提示AD神经退行性变的共同模式。