Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models
Debashis Dutta, … , Sridevi Dasarathy, Kalipada Pahan
Debashis Dutta, … , Sridevi Dasarathy, Kalipada Pahan
Published August 8, 2023
Citation Information: J Clin Invest. 2023;133(18):e161987. https://doi.org/10.1172/JCI161987.
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Research Article Inflammation Neuroscience

Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models

Abstract

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.

Authors

Debashis Dutta, Malabendu Jana, Ramesh Kumar Paidi, Moumita Majumder, Sumita Raha, Sridevi Dasarathy, Kalipada Pahan

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Figure 6

Cognition is improved in PS19 animals by wtTIDM administration.

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Cognition is improved in PS19 animals by wtTIDM administration. (A) PS19...
(A) PS19 mice (7 months old) were given intranasal administration of wtTIDM or mTIDM (0.1 mg/kg) for 1 month, and then spatial memory of these animals was evaluated by conducting Barnes maze analysis; the heatmaps demonstrate the exploratory activity of the animals in the maze to find out the goal box (n = 7 animals per group). Cognitive parameters including total errors made before reaching the goal box (B) and latency time for the reaching goal box (C) are shown in the diagrams. (D) NORT was conducted to explore the memory-retention ability of the experimental mice. Time spent by each mouse with the familiar object (E) and with the novel object.\ (F) was recorded for determining the cognitive performance of different groups of mice (n = 6 animals per group). Locomotor activity of mice was assessed by performing an open-field test (G), in which parameters including distance (H), velocity (I), and center frequency (J) in the arena were recorded. (K) Motor coordination was evaluated by rotarod test (n = 7 animals per group). Statistical analyses were performed with 1-way ANOVA followed by Tukey’s multiple-comparison analysis. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with the designated groups. Values are presented as mean ± SEM.