Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology.
Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology.
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DOI：
10.1172/jci96209
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Pahan K
中科院分区：
文献类型：
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作者：
Rangasamy SB;Jana M;Roy A;Corbett GT;Kundu M;Chandra S;Mondal S;Dasarathi S;Mufson EJ;Mishra RK;Luan CH;Bennett DA;Pahan K
TLR 2激活的诱导依赖于其与衔接蛋白MyD 88的结合。我们已经发现，TLR 2和MyD 88水平在阿尔茨海默病（AD）患者的海马和皮质中以及在AD的5XFAD小鼠模型中升高。由于不存在TLR 2的特异性抑制剂，为了从治疗角度靶向诱导的TLR 2，我们工程化了对应于MyD 88（TIDM）的TLR 2相互作用结构域的肽，其仅结合TLR 2的BB环，而不结合其他TLR。有趣的是，WT TIDM肽抑制由纤维状Aβ1-42和脂磷壁酸诱导的小胶质细胞活化，但不抑制1-甲基-4-苯基吡啶鎓、dsRNA、细菌脂多糖、鞭毛蛋白或CpG DNA。鼻内给药后，WT TIDM肽到达海马，减少海马胶质细胞活化，降低Aβ负荷，减弱神经元凋亡，并改善5XFAD小鼠的记忆和学习。然而，WT TIDM肽在缺乏TLR 2的5XFAD小鼠中无效。除了在5XFAD小鼠中的作用外，WT TIDM肽还抑制了患有实验性过敏性脑脊髓炎和胶原诱导的关节炎的小鼠的疾病过程。因此，WT TIDM肽选择性靶向先天免疫系统1组分的活化状态可能有益于AD以及TLR 2/MyD 88信号传导在疾病发病机制中起作用的其他疾病。
Induction of TLR2 activation depends on its association with the adapter protein MyD88. We have found that TLR2 and MyD88 levels are elevated in the hippocampus and cortex of patients with Alzheimer’s disease (AD) and in a 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from a therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. Interestingly, WT TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, dsRNA, bacterial lipopolysaccharide, flagellin, or CpG DNA. After intranasal administration, WT TIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, WT TIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to its effects in 5XFAD mice, WT TIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of the activated status of 1 component of the innate immune system by WT TIDM peptide may be beneficial in AD as well as other disorders in which TLR2/MyD88 signaling plays a role in disease pathogenesis.