Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Aβ accumulation through suppression of neuronal γ-secretase activity and promotion of microglial amyloid-β phagocytosis and ameliorates cognitive impairment in a mouse mode
Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Aβ accumulation through suppression of neuronal γ-secretase activity and promotion of microglial amyloid-β phagocytosis and ameliorates cognitive impairment in a mouse mode
复制标题
Alpha7 烟碱乙酰胆碱受体特异性激动剂 DMXBA (GTS-21) 通过抑制神经元 γ 分泌酶活性和促进小胶质细胞淀粉样蛋白 -β 吞噬作用来减弱 Aβ 积累，并改善小鼠模型中的认知障碍
DOI：
10.1016/j.neurobiolaging.2017.10.021
复制
发表时间：
2018
期刊：
影响因子：
4.2
通讯作者：
et al.
中科院分区：
文献类型：
--
作者：
Takata K.;et al.
我们之前在阿尔茨海默病（AD）转基因小鼠模型中证明，刺激尼古丁乙酰胆碱受体（nAChRs）增加大鼠小胶质细胞中淀粉样蛋白-β (a β)吞噬，并与脑a β减少和记忆功能障碍改善密切相关。在这里，我们研究了参与这些有益作用的nachr亚型。在原代培养的大鼠小胶质细胞中，α7 nAChR选择性受体拮抗剂3-[（2,4-二甲氧基）苄基]-二盐酸猪脑碱（DMXBA）促进了α β和荧光胶乳珠的吞噬，而α7 nAChR选择性拮抗剂抑制了α β的吞噬。在AD转基因小鼠模型中，给药DMXBA减轻了脑a β负荷和记忆功能障碍。此外，DMXBA还能抑制人神经母细胞瘤细胞和转基因小鼠脑组织中γ-分泌酶的活性。上述结果提示，α7 nachr的选择性激活促进了小胶质细胞对α β的吞噬，抑制了神经元γ-分泌酶的活性，从而减轻了脑内α β的负担，减轻了认知功能障碍。因此，我们提出神经元和小胶质α7 nachr作为治疗AD的新靶点。
We previously demonstrated that stimulation of nicotinic acetylcholine receptors (nAChRs) increases amyloid-β (Aβ) phagocytosis in rat microglia and is closely associated with the decrease of brain Aβ and amelioration of memory dysfunction in a transgenic mouse model of Alzheimer's disease (AD). Here, we examined the subtypes of nAChRs involved in these beneficial effects. In primary cultures of rat microglia, the α7 nAChR selective agonist 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA) promoted Aβ and fluorescent latex bead phagocytosis, whereas selective α7 nAChR antagonists suppressed the enhanced Aβ phagocytosis. In a transgenic mouse model of AD, administration of DMXBA attenuated brain Aβ burden and memory dysfunction. Moreover, DMXBA suppressed γ-secretase activity in solubilized fractions of human neuroblastoma cells and transgenic mouse brain. These results suggested that selective activation of α7 nAChRs promoted microglial Aβ phagocytosis and suppressed neuronal γ-secretase activity to contribute to the attenuation of the brain Aβ burden and cognitive impairment. Thus, we propose neuronal and microglial α7 nAChRs as new therapeutic targets in the treatment of AD.