Mechanism of Action of ABeta*56 in Alzheimer's Disease

这项建议的长期目标是了解阿尔茨海默氏症患者记忆丧失的原因 疾病(AD)。 2006年，我们已经证明，我们命名为A3*56的特定淀粉样β蛋白(A3)组装很可能是 阿尔茨海默病小鼠模型Tg2576认知功能减退的原因作为该奖项指导阶段的一部分 (K99)，我们证实在人脑组织和脑脊液中存在Alphabeta*56。我们 在三个临床组中测量包括Alphabeta*56在内的几种寡聚体的显著程度：非认知性 年龄匹配正常受损者(NCI)、轻度认知障碍(MCI)和阿尔茨海默病(AD)。我们 研究发现，Alphabeta*56的水平在5“^岁的生命中上升，在这段时间里，记忆力下降的第一个迹象是 明显(也称为急性心肌梗死)，其水平随着疾病的进展而下降。三聚体在MCI中达到顶峰 随着痴呆症的加重，脑组织中二聚体的含量逐渐增加。此外，我们还鉴定了一种可能的受体 A3*56。无论是在转基因动物的组织中，还是在人脑中。 通过这一应用，我们建议破译Alphabeta*56在体外和体内结合的作用机制。 活体范例。最后，我们计划评估包括Alphabeta*56在内的Alphabeta寡聚体是否代表A3 连接疾病的两个表型特征的实体，即淀粉样斑块和 神经原纤维缠结。

The broad long-term objective of this proposal is to understand how memory loss occurs in Alzheimer's disease (AD). In 2006, we have shown that a specific amyloid beta (A3) assembly that we named A3*56 was likely the cause of cognitive decline in the mouse model of AD, Tg2576. As part of the mentored phase of this award (K99), we confirmed the existence of Alphabeta*56 in the human brain tissues and cerebrospinal fluid. We measured the prominence of several oligomers including Alphabeta*56 in three clinical groups: non-cognitively impaired age-matched normals (NCI), mild cognitive impairment (MCI) and Alzheimer's disease(AD). We found that Alphabeta*56 levels rise during the 5"^ decade of life during which the first signs of memory decline is noticeable (also known as AAMI) and its levels decrease with disease progression. Trimers peaked in MCI brain tissues while dimers slowly increased with dementia. In addition, we identified a putative receptor for A3*56. both in tissues from transgenic animals as well as in human brains. With this application, we propose to decipher the mechanism of action of Alphabeta*56 combining in vitro and in vivo paradigms. Finally we plan to evaluate whether Alphabeta oligomers including Alphabeta*56 represent the A3 entity(ies) connecting the two phenotypic hallmarks ofthe disease, namely amyloid plaques and neurofibrillary tangles.