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AB*56的特定淀粉样β(AB)组件很可能是 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)，我们证实了AB*56在人脑组织和脑脊液中的存在。我们 在三个临床组中测量包括AB*56在内的几个寡聚体的显著程度：非认知 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 发现AB*56水平在人的第五个十年期间上升，在此期间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 AB*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AB*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AB*56在内的AB齐聚物是否代表AB 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 (AB) assembly that we named AB*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 AB*56 in the human brain tissues and cerebrospinal fluid. We measured the prominence of several oligomers including AB*56 in three clinical groups: non-cognitively impaired age-matched normals (NCI), mild cognitive impairment (MCI) and Alzheimer's disease(AD). We found that AB*56 levels rise during the 5th 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 AB*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 AB*56 combining in vitro and in vivo paradigms. Finally we plan to evaluate whether AB oligomers including AB*56 represent the AB entity(ies) connecting the two phenotypic hallmarks of the disease, namely amyloid plaques and neurofibrillary tangles.