Amyloid beta-protein deposition and toxicity in animal models of Alzheimer's disease

APP转基因小鼠是阿尔茨海默病（AD）的动物模型。在这些小鼠中产生淀粉样b蛋白（Aβ）聚集体，并诱导锥体神经元的树突状改变。使用小鼠模型进行细胞内和细胞外Aβ沉积，我们能够证明细胞外而非细胞内Ab聚集体诱导树突变性和突触丢失。我们发现大概生理上发生的抗体聚集在野生型小鼠和对照患者的大脑。在AD病例和APP转基因小鼠中，发现了具有异常构象的神经变性Ab-聚集体迹象。为了进一步表征这些异常Aβ聚集体，将对人AD和对照脑组织进行生物病理学和生物化学分析，以确定不同的Aβ聚集体构象。为了测试异常Ab聚集体是否能够支持具有细胞内t蛋白聚集体的AD相关神经病理学的发展，将不同的APP转基因小鼠模型与t转基因小鼠杂交。将分析哪种类型的Aβ表达影响t病理学。最后，年轻的免疫APP转基因小鼠表现出较少的树突状病变比非免疫的。我们想通过分析这些小鼠的突触密度和3个营养不良树突的数量来证实这一初步发现。在这样做的过程中，我们希望进一步阐明Ab毒性的机制，并验证可能的AD治疗靶点的价值。

The APP-transgenic mouse is an animal model for Alzheimer's disease (AD). Amyloid b-protein (Aβ) aggregates are produced in these mice and induce dendritic alterations of pyramidal neurons. Using mouse models for intra- as well as for extracellular Aβ-deposition we were able to show that extracellular but not intracellular Ab-aggregates induce dendritic degeneration and synapse loss. We found presumably physiologically occurring Ab-aggregates in the brain of wildtype mice and control patients. In AD cases and in APP-transgenic mice developing signs of neurodegeneration Ab-aggregates with an abnormal conformation were identified. To further characterize these abnormal Aβ-aggregates human AD and control brain tissue will be analyzed biophysically and biochemically for distinct Aβ-aggregate conformations. To test whether abnormal Ab-aggregates are capable of supporting the development of AD-related neurofibrillary pathology with intracellular t-protein aggregates different APP-transgenic mouse models will be crossbred with t-transgenic mice. It will be analyzed which type of Aβ-expression influences t-pathology. Finally, young immunized APP-transgenic mice showed less dendritic pathology than non-immunized ones. We want to confirm this preliminary finding by analyzing the synapse density and the number of 3 dystrophic dendrites in these mice. In so doing, we want to further clarify the mechanisms of Ab- toxicity and to verify the value of possible therapeutic targets for AD.