Abstract：
Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer\'s disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-β peptide (Aβ1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aβ1-42 monomers could improve the impaired memory not only in cDKO mice without Aβ1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aβ1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aβ1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aβ1-42 level due to Aβ1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, \"loss-of-function\" of Aβ1-42 should be avoided when designing therapies aimed at reducing Aβ1-42 burden in AD.
摘要：
越来越多的证据表明，脑淀粉样蛋白斑块与阿尔茨海默病（AD）之间的相关性较差。Presenilin1（PS1）和Presenilin2（PS2）条件性双敲除（cDKO）小鼠表现出42个氨基酸的淀粉样β肽（Aβ1-42）水平降低和AD样症状，表明与AD的淀粉样蛋白级联假说不同的病理机制。在这里，我们发现外源合成Aβ1-42单体不仅可以改善没有Aβ1-42沉积的cDKO小鼠的记忆受损，而且还可以改善具有Aβ1-42沉积的APP/PS1/Tau三重转基因3×Tg-AD小鼠的记忆受损。由α7-nAChR介导。我们的发现首次证明可溶性Aβ1-42水平降低是cDKO小鼠认知功能障碍的主要原因。并支持以下观点：由于Aβ1-42沉积导致的低可溶性Aβ1-42水平也可能导致3×Tg-AD小鼠的认知缺陷。因此,在设计旨在减少AD中Aβ1-42负担的疗法时，应避免Aβ1-42的“功能丧失”。
