Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP.
Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP.
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DOI：
10.1038/ncomms14726
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发表时间：
2017-03-13
影响因子：
16.6
通讯作者：
Gouras GK
中科院分区：
文献类型：
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作者：
Klementieva O;Willén K;Martinsson I;Israelsson B;Engdahl A;Cladera J;Uvdal P;Gouras GK
降低阿尔茨海默病（AD）患者大脑中聚集的易聚集Aβ肽水平一直是实验治疗的主要目标。另一种方法可能是稳定Aβ的生理构象。迄今为止，脑中Aβ的生理状态仍不清楚，因为用于处理脑组织以测定Aβ聚集体构象的可用方法本身可以改变聚集体的结构和/或组成。本文利用同步辐射傅立叶变换红外显微光谱、非变性凝胶电泳和构象特异性抗体等技术，研究了AD转基因小鼠模型脑内Aβ和淀粉样前体蛋白（APP）的生理构象在淀粉样斑块形成前的变化。此外，在淀粉样斑块形成之前，脑内局灶性Aβ聚集物定位于突触终末。斑块形成前Aβ和APP状态的这些变化可能为AD治疗提供新的靶点。研究淀粉样蛋白β（Aβ）和淀粉样蛋白前体蛋白（APP）的生理学确认通常使用可能破坏其构象的技术。在这里，作者使用非破坏性显微镜方法来研究阿尔茨海默病小鼠模型中Aβ和APP的确认。
Reducing levels of the aggregation-prone Aβ peptide that accumulates in the brain with Alzheimer's disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of Aβ. To date, the physiological state of Aβ in brain remains unclear, since the available methods used to process brain tissue for determination of Aβ aggregate conformation can in themselves alter the structure and/or composition of the aggregates. Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Aβ and amyloid precursor protein (APP) in brain of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal Aβ aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of Aβ and APP that occur prior to plaque formation may provide novel targets for AD therapy. Studying the physiological confirmation of amyloid β (Aβ) and amyloid precursor protein (APP) often uses techniques that could disrupt their conformation. Here, the authors use non-destructive microscopy approaches to study the confirmation of Aβ and APP in mouse models of Alzheimer's disease.