Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition.
Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition.
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Aβ 抑制和大脑先天免疫激活的结合显着减弱淀粉样斑块沉积。
DOI：
10.1016/j.ajpath.2017.08.010
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Das,Pritam
中科院分区：
文献类型：
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作者：
Verbeeck,Christophe;Carrano,Anna;Chakrabarty,Paramita;Jankowsky,JoannaL;Das,Pritam
目前正在进行抗a β临床试验，以确定预防淀粉样蛋白沉积是否有助于阻止阿尔茨海默病的进展。临床和临床前研究都表明，抗淀粉样蛋白策略只有在疾病进程的早期阶段作为一级预防策略才有效。由于这种方法难以实施，因此还需要针对疾病后期阶段的二级预防战略。在这项研究中，我们研究了将大脑先天免疫激活与同时抑制Aβ结合是否可以增强斑块清除并改善中度淀粉样蛋白病理障碍小鼠的病理结果。从5月龄开始，用强力霉素（dox）处理脱淀粉样前体蛋白转基因小鼠，以抑制淀粉样前体蛋白/Aβ的进一步产生，同时向小鼠颅内注射表达小鼠IL-6 （AAV1-mIL-6）的腺相关病毒1。3个月后，Aβ抑制和AAV1-mIL-6联合治疗的小鼠斑块病理障碍明显少于仅dox或AAV1-mIL-6组。与未经治疗的对照组相比，AAV1-mIL-6 + dox联合治疗可降低总斑块负担60%。单独使用dox或AAV1-mIL-6治疗的效果不如联合使用。我们的研究结果表明，在a β抑制的情况下，mIL-6的上调能够改善斑块清除，这是一种协同机制。
Anti-Aβ clinical trials are currently under way to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and preclinical studies suggest that antiamyloid strategies are only effective if started at early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Aβ suppression could enhance plaque clearance and could improve pathologic outcomes in mice with moderate amyloid pathologic disorder. Starting at 5 months of age, tet-off amyloid precursor protein transgenic mice were treated with doxycycline (dox) to suppress further amyloid precursor protein/Aβ production, and at the same time mice were intracranially injected with adeno-associated virus 1 expressing murine IL-6 (AAV1-mIL-6). Three months later, mice treated with the combination of Aβ suppression and AAV1-mIL-6 showed significantly less plaque pathologic disorder than dox or AAV1-mIL-6 only groups. The combination of AAV1-mIL-6 + dox treatment lowered total plaque burden by >60% versus untreated controls. Treatment with either dox or AAV1-mIL-6 alone was less effective than the combination. Our results suggest a synergistic mechanism by which the up-regulation of mIL-6 was able to improve plaque clearance in the setting of Aβ suppression.