Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer's disease-related mouse models.
Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer's disease-related mouse models.
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DOI：
10.1172/jci161987
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发表时间：
2023-09-15
影响因子：
15.9
通讯作者：
Pahan, Kalipada
中科院分区：
文献类型：
--
作者：
Dutta, Debashis;Jana, Malabendu;Paidi, Ramesh Kumar;Majumder, Moumita;Raha, Sumita;Dasarathy, Sridevi;Pahan, Kalipada
神经胶质活化和炎症与神经元中的神经纤维缠结（NFT）形成一致。然而，tau纤维和神经胶质细胞之间相互作用的机制知之甚少。在这里，我们发现tau预形成的纤维（PFF）通过特异性激活TLR 2/MyD 88而不是TLR 4/MyD 88途径引起小胶质细胞中的炎症诱导。因此，MyD 88的WT TLR 2相互作用结构域（wtTIDM）肽抑制tau PFF诱导的TLR 2/MyD 88/NF-κB途径的活化，导致炎症减少。发现在表达P301 S tau的PS19小鼠中鼻内施用wtTIDM抑制神经胶质增生和炎性标志物，以及减少海马中的致病性tau，从而改善PS19小鼠的认知行为。在缺乏TLR 2的PS19小鼠中，wtTIDM对tau病理学的抑制作用不存在，这加强了TLR 2在体内wtTIDM介导的作用中的基本参与。进一步研究其机制，我们发现tau启动子具有潜在的NF-κ B结合位点，并且促炎分子通过NF-κB增加神经元中tau的转录。这些结果表明，tau诱导的神经炎症和神经病理学需要TLR 2，并且神经炎症通过NF-κB直接上调神经元中的tau，突出了炎症和tau病变之间的直接联系。
Glial activation and inflammation coincide with neurofibrillary tangle (NFT) formation in neurons. However, the mechanism behind the interaction between tau fibrils and glia is poorly understood. Here, we found that tau preformed fibrils (PFFs) caused induction of inflammation in microglia by specifically activating the TLR2/MyD88, but not the TLR4/MyD88, pathway. Accordingly, the WT TLR2–interacting domain of MyD88 (wtTIDM) peptide inhibited tau PFF–induced activation of the TLR2/MyD88/NF-κB pathway, resulting in reduced inflammation. Nasal administration of wtTIDM in P301S tau–expressing PS19 mice was found to inhibit gliosis and inflammatory markers, as well as to reduce pathogenic tau in the hippocampus, resulting in improved cognitive behavior in PS19 mice. The inhibitory effect of wtTIDM on tau pathology was absent in PS19 mice lacking TLR2, reinforcing the essential involvement of TLR2 in wtTIDM-mediated effects in vivo. Studying the mechanism further, we found that the tau promoter harbored a potential NF-κB–binding site and that proinflammatory molecules increased transcription of tau in neurons via NF-κB. These results suggest that tau-induced neuroinflammation and neuropathology require TLR2 and that neuroinflammation directly upregulates tau in neurons via NF-κB, highlighting a direct connection between inflammation and tauopathy.
影响因子：
6.1
作者：
Dutta D;Majumder M;Paidi RK;Pahan K
通讯作者：
Pahan K