Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models
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 specif...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI161987 |
| _version_ | 1797634418365431808 |
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| author | Debashis Dutta Malabendu Jana Ramesh Kumar Paidi Moumita Majumder Sumita Raha Sridevi Dasarathy Kalipada Pahan |
| author_facet | Debashis Dutta Malabendu Jana Ramesh Kumar Paidi Moumita Majumder Sumita Raha Sridevi Dasarathy Kalipada Pahan |
| author_sort | Debashis Dutta |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:22Z |
| format | Article |
| id | doaj.art-2c308afde27e4306aefbbd9e0739ba70 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:22Z |
| publishDate | 2023-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-2c308afde27e4306aefbbd9e0739ba702023-11-07T16:20:51ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-09-0113318Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse modelsDebashis DuttaMalabendu JanaRamesh Kumar PaidiMoumita MajumderSumita RahaSridevi DasarathyKalipada PahanGlial 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.https://doi.org/10.1172/JCI161987InflammationNeuroscience |
| spellingShingle | Debashis Dutta Malabendu Jana Ramesh Kumar Paidi Moumita Majumder Sumita Raha Sridevi Dasarathy Kalipada Pahan Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models The Journal of Clinical Investigation Inflammation Neuroscience |
| title | Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models |
| title_full | Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models |
| title_fullStr | Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models |
| title_full_unstemmed | Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models |
| title_short | Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models |
| title_sort | tau fibrils induce glial inflammation and neuropathology via tlr2 in alzheimer s disease related mouse models |
| topic | Inflammation Neuroscience |
| url | https://doi.org/10.1172/JCI161987 |
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