Mechanisms of amyloid-beta clearance.

超出提供的空间。过度表达APP的转基因小鼠模型会以一种与年龄相关的方式发展老年斑，类似于在阿尔茨海默病(AD)患者中发现的那些。最近的证据表明，主动或被动免疫疗法显著阻止了转基因小鼠中淀粉样蛋白13的沉积。清除阿尔茨海默病患者中现有的淀粉样蛋白13沉积，除了防止新的斑块形成外，将是有效治疗的关键。观察治疗前后的老年斑是测量现有沉积物清除情况的唯一直接方法，但直到最近，这还不可能。我们已经开发了新的多光子显微镜技术，可以对单个斑块进行纵向体内成像。使用这种方法，我们在转基因小鼠中展示了在将抗体单一应用于皮质后3-5天清除现有斑块的方法。在这个应用中，我们建议测试关于清除机制的假设。目的1根据我们的观察，添加F(ab‘)2片段也可以发生清除，这表明Fc介导的机制不是必要的。我们提出了一个模型，其中清除是一个两步过程的结果，包括通过直接的生物物理相互作用解聚淀粉样蛋白-13沉积，然后主动去除淀粉样蛋白。目的2询问系统免疫，而不是局部应用抗体到皮质，是否会导致清除；如果是，我们将确定必要的滴度和最佳表位。目的3利用几个实验室的体外结果，证明淀粉样蛋白-13结合化合物防止或逆转淀粉样蛋白纤维的形成。我们将在体内测试它们是否为解聚剂。这一结果将对旨在消除老年斑和阿尔茨海默病相关神经损伤的治疗方法的发展产生重大影响。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. Transgenic mouse models over-expressing APP develop senile plaques in an age-dependent fashion similar to those found in patients with Alzheimer's disease (AD). Recent evidence shows that active or passive immunotherapy dramatically prevents amyloid-13 deposition in transgenic mice. Clearance of existing amyloid-13 deposits present in Alzheimer's disease patients, in addition to prevention of new plaque formation, will be critical for an effective treatment. Observing senile plaques before and after treatment is the only direct way to measure clearance of existing deposits, but until recently this has not been possible. We have developed novel multiphoton microscopy techniques that allow longitudinal in vivo imaging of individual plaques. Using this approach, we demonstrated clearance of existing plaques in transgenic mice 3-5 days after a single application of antibodies to the cortex. In this application, we propose to test hypotheses about the mechanism of clearance. Aim 1 follows from our observation that clearance can also occur with addition of F(ab')2 fragments, suggesting that Fc-mediated mechanisms are not necessary. We propose a model whereby clearance results from a two-step process involving disaggregation of amyloid-13 deposits via direct biophysical interaction followed by active removal of the amyloid. Aim 2 asks whether systemic immunization, rather than topical application of antibody to cortex, will lead to clearance; if so, we will determine necessary titers and optimal epitopes. Aim 3 takes advantage of in vitro results from several laboratories demonstrating that amyloid-13 binding compounds prevent or reverse formation of amyloid fibrils. We will test whether they are disaggregating agents in vivo. The results will strongly impact the development of treatments aimed at removing senile plaques and the associated neurological damage in Alzheimer's disease. PERFORMANCE SITE ========================================Section End===========================================