APP Metabolism in Transgenic Down Syndrome Mouse Models

描述(申请人提供)：小的Aβ多肽在大脑中积累在β-淀粉样斑块中是阿尔茨海默病(AD)的一个不变特征，AD是影响600多万美国人的最常见的神经退行性变类型。Aβ是由淀粉样前体蛋白(APP)的蛋白水解性加工而来的。患有唐氏综合症(DS；21三体)的人在他们生命的第四或第五年不可避免地会发展为AD病理，包括β-淀粉样斑块。App基因位于人类21号染色体上，一般认为App的这一额外基因拷贝机械地导致了DS患者的AD。利用人类DS的小鼠模型，如Ts65Dn小鼠，它是与人类21号染色体DS关键区域同源的小鼠16号染色体的三体，将在完整的中枢神经系统中检测APP的新陈代谢和Abeta的产生。APP代谢物水平将被确定为Ts65Dn小鼠衰老的函数，并将检测Ts65Dn小鼠体内APP和APP代谢物(分泌型APP片段、C-末端APP片段、Abeta)周转率的变化(目标1)。Ts65Dn小鼠还表现出内吞功能异常，选择性地出现在AD和DS中，以及年龄依赖性的基底前脑胆碱能神经元变性。鉴于先前已经证明APP的蛋白降解过程可以发生在早期的内小体中，Ts65Dn模型中神经元内吞作用的变化和APP代谢之间的联系将使用免疫定位技术以及亚细胞分离来研究(目标2)。Ts65Dn小鼠APP代谢异常与神经退行性变有机械联系的假设将通过使用抗小鼠Abeta单抗(Aim 3)被动接种降低中枢Abeta水平来检验，从而在该模型中建立神经退行性变与Abeta水平/APP代谢异常之间的联系。这些研究将描述体内脑内APP代谢的特征，并测试APP代谢错误是DS模型中基底前脑胆碱能神经变性的原因这一观点。这些发现将对DS的AD发病机制有重要意义，并可能提示AD常见的神经退行性变方式。

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.