NOVEL AB FRAGMENTS AS MEDIATORS OF ALZHEIMERS DISEASE

淀粉样β（Abeta）肽在老年斑中的沉积是阿兹海默病（AD）发病机制中的重要事件，并且Abeta是由β-淀粉样前体蛋白（APP）通过最近鉴定的称为BACE 1（β-位点APP裂解酶1）的β-分泌酶和含有早老素（PS）的γ-分泌酶复合物连续裂解而产生的。令人惊讶的是，BACE 1显示在A β的Asp 1和Glu 11处切割APP，产生全长A β 1 -40/42以及N末端截短的A β 11 -40/42肽。然而，尽管事实上已检测到高浓度的Abeta 11 -40/42肽 尽管AD和唐氏综合征患者脑中的水平不同，但某些家族性AD相关的PS1和APP突变增加了N-末端截短的Abeta肽的沉积，并且这些肽比全长Abeta肽更容易聚集，调节Abeta 11 -40/42的产生和聚集的机制及其在AD发病机制中的作用仍然未知。在这项竞争性更新申请中，项目2将测试Abeta 11 -40/42可能在增加Abeta原纤维形成、Abeta聚集和Abeta毒性方面发挥主要作用的假设。为了实现我们的目标，我们将评估和比较轻度认知障碍（MCI）、AD、唐氏综合征患者和无认知障碍（NCI）对照患者脑中的A β 11 - 40/42与A β 1 -40/42的分布。我们还将比较Abeta 11 -40/42与Abeta 1 -40/42肽的结构和絮凝特性。将开发转基因动物模型以评估Abeta 11 -40/42肽在老年斑形成、认知功能和神经变性中的作用。最后，我们将评估A β 1 -40/42和A β 11 -40/42寡聚体在AD淀粉样变性转基因小鼠模型的学习和记忆中的特定作用。这些研究的成功完成将有助于确定A β 11 -40/42肽在AD发病机制中的作用。

The deposition of amyloid beta (Abeta) peptides in senile plaques is a seminal event in the pathogenesis of Azheimer's disease (AD) and Abeta is generated from beta-amyloid precursor protein (APP) by the sequential cleavage by a recently identified beta-secretase known as BACE1 (beta-site APP cleavage enzyme 1) and the presenilin (PS) containing gamma-secretase complex. Surprisingly, BACE1 was shown to cleavage APP at both Asp 1 and Glu 11 of Abeta generating both full length Abeta1-40/42 as well as the N-terminally truncated Abeta11-40/42 peptides. However, despite the fact that Abeta11-40/42 peptides have been detected at high levels in brains of AD and Down's syndrome patients, that certain familial AD associated PS1 and APP mutations increase the deposition of the N-terminal truncated Abeta peptides and that these peptides aggregate more readily than full length Abeta peptides, the mechanism regulating the production and aggregation of Abeta11-40/42 and its role in AD pathogenesis remains unknown. In this competitive renewal application, Project 2 will test the hypothesis that Abeta11-40/42 may play a major role in increasing Abeta fibril formation, Abeta aggregation and Abeta toxicity. To accomplish our goals, we will assess and compare the distribution of Abeta11-40/42 with Abeta1-40/42 in brains of patients with mild cognitive impairment (MCI), with AD, with Down's syndrome and in control patients with no cognitive impairments (NCI). We will also compare the structure and the fibrillization properties of Abeta11-40/42 with the Abeta1-40/42 peptides. Transgenic animal models will be developed to assess the role of Abeta11-40/42 peptides in senile plaque formation, in cognitive function and in neurodegeneration. Finally we will evaluate the specific role of Abeta1-40/42 and Abeta11-40/42 oligomers in learning and memory in transgenic mouse models of AD amyloidosis. Successful completion of the proposed studies will help define the roles of Abeta11-40/42 peptides in the pathogenesis of AD.