M2-Like Microglia Polarization Attenuates Neuropathic Pain Associated with Alzheimer's Disease
M2-Like Microglia Polarization Attenuates Neuropathic Pain Associated with Alzheimer's Disease
复制标题
M2样小胶质细胞极化减轻与阿尔茨海默病相关的神经病理性疼痛
DOI：
10.3233/jad-200099
复制
发表时间：
2020-01-01
影响因子：
4
通讯作者：
Ge, Zhao-Ming
中科院分区：
文献类型：
--
作者：
Jin, Jing;Guo, Jia;Ge, Zhao-Ming
许多阿尔茨海默病（AD）患者患有持续性神经性疼痛（NP），其至少部分是由小胶质细胞介导的。然而，确切的潜在机制尚不清楚。此外，通过调节小胶质细胞治疗AD相关NP的临床可转化方法不可用。在这里，在多西环素诱导的AD小鼠模型（rTg 4510）中，我们显示了NP的发展。我们发现，CA 3区域中的小胶质细胞的总数没有增加，而是极化为促炎Ml样表型，伴随着促炎细胞因子的产生和分泌的增加。为了检查这种小胶质细胞极化是否在AD相关NP中起重要作用，我们产生了腺相关病毒（AAV）血清型PHP.B（能够穿过血脑屏障），在小胶质细胞特异性TMEM 119启动子下携带DNA甲基转移酶1（DNMT 1）的shRNA（AAV-pTMEM 119-shDNMT 1），它特异性靶向小胶质细胞，并在多西环素处理的rTg 4510小鼠的体外和体内诱导M2样极化。静脉内输注AAV-pTMEM 119-shDNMT 1诱导小胶质细胞的M2极化，并在多西环素处理的rTg 4510小鼠中减弱AD相关的行为障碍和NP。因此，我们的数据表明，AD相关的NP可以通过小胶质细胞的M2极化来治疗。
Many Alzheimer's disease (AD) patients suffer from persistent neuropathic pain (NP), which is mediated, at least partially, but microglia. Nevertheless, the exact underlying mechanism is unknown. Moreover, a clinically translatable approach through modulating microglia for treating AD-associated NP is not available. Here, in a doxycycline-induced mouse model (rTg4510) for AD, we showed development of NP. We found that the total number of microglia in the CA3 region was not increased, but polarized to pro-inflammatory Ml-like phenotype, with concomitant increases in production and secretion of pro-inflammatory cytokines. To examine whether this microglia polarization plays an essential role in the AD-associated NP, we generated an adeno-associated virus (AAV) serotype PHP.B (capable of crossing the blood-brain barrier) carrying shRNA for DNA methyltransferase 1 (DNMT1) under a microglia-specific TMEM119 promoter (AAV-pTMEM119-shDNMT1), which specifically targeted microglia and induced a M2-like polarization in vitro and in vivo in doxycycline-treated rTg4510 mice. Intravenous infusion of AAV-pTMEM119-shDNMT1 induced M2-polarization of microglia and attenuated both AD-associated behavior impairment but also NP in the doxycycline-treated rTg4510 mice. Thus, our data suggest that AD-associated NP may be treated through M2-polarization of microglia.