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

这项提议的广泛的长期目标是了解阿尔茨海默氏症是如何发生记忆丧失的 疾病（AD）。 在2006年，我们已经表明，一种我们命名为AB*56的特定淀粉样蛋白β（AB）组装体可能是 AD小鼠模型中认知能力下降的原因，Tg2576。作为该奖项指导阶段的一部分， (K99)结果表明，AB*56在人脑组织和脑脊液中均存在。我们 在三个临床组中测量了包括AB*56在内的几种寡聚体的显著性：非认知性 受损的年龄匹配的正常人（NCI）、轻度认知障碍（MCI）和阿尔茨海默病（AD）。我们 发现AB*56水平在生命的第五个十年上升，在此期间记忆力下降的第一个迹象是 值得注意的（也称为AAMI），其水平随着疾病进展而下降。三聚体在MCI中达到峰值 而二聚体则随着痴呆的发生而缓慢增加。此外，我们还鉴定了一种假定的受体， AB*56。无论是在转基因动物的组织中还是在人脑中。 通过这种应用，我们建议在体外和体内破译AB*56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寡聚体是否代表AB 实体连接疾病的两个表型标志，即淀粉样蛋白斑块和 神经系统缠结

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.