Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models
Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models
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DOI：
10.1016/j.neurobiolaging.2018.06.002
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发表时间：
2018-10-01
影响因子：
4.2
通讯作者：
Forloni, Gianluigi
中科院分区：
文献类型：
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作者：
Balducci, Claudia;Santamaria, Giulia;Forloni, Gianluigi
β-淀粉样蛋白低聚物（A β Os）和神经炎症是阿尔茨海默病（AD）中的两个主要罪魁祸首。多西环素（DOXY）是四环素类的第二代抗生素，其是在许多临床试验中测试用于许多不同病理的有希望的药物。DOXY具有抗淀粉样蛋白生成的特性，并且更好地穿过血脑屏障，但其功效从未在AD小鼠中进行过测试。我们在此表明，15至16个月大的APP/PS1 dE 9（APP/PS1）AD小鼠在不同的治疗方案下接受DOXY恢复了记忆，而没有斑块减少。急性DOXY治疗也足以改善APP/PS1小鼠的记忆，表明对可溶性A β Os的作用。这在A β O诱导的小鼠模型中得到证实，其中A β O介导的记忆障碍被DOXY预处理消除。虽然A β O通过神经胶质活化诱导记忆障碍，但评估DOXY的抗炎作用，我们发现在A β O治疗和APP/PS1小鼠中，记忆恢复与较低的神经炎症相关。我们的数据促进DOXY作为一个有希望的重新定位的药物抵消关键的神经病理性AD目标。(C)2018爱思唯尔公司All rights reserved.
beta-Amyloid oligomers (A beta Os) and neuroinflammation are 2 main culprits to counteract in Alzheimer's disease (AD). Doxycycline (DOXY) is a second generation antibiotic of the tetracycline class that are promising drugs tested in many clinical trials for a number of different pathologies. DOXY is endowed with antiamyloidogenic properties and better crosses the blood-brain barrier, but its efficacy has never been tested in AD mice. We herein show that 15- to 16-month-old APP/PS1dE9 (APP/PS1) AD mice receiving DOXY under different treatment regimens recovered their memory without plaque reduction. An acute DOXY treatment was, also, sufficient to improve APP/PS1 mouse memory, suggesting an action against soluble A beta Os. This was confirmed in an A beta O-induced mouse model, where the A beta O-mediated memory impairment was abolished by a DOXY pretreatment. Although A beta Os induce memory impairment through glial activation, assessing the anti-inflammatory action of DOXY, we found that in both the A beta O-treated and APP/PS1 mice, the memory recovery was associated with a lower neuroinflammation. Our data promote DOXY as a hopeful repositioned drug counteracting crucial neuropathological AD targets. (C) 2018 Elsevier Inc. All rights reserved.