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.
View: Text | PDF
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

×

Figure 3

The wtTIDM nasal administration suppresses gliosis and inflammation in the hippocampus of PS19 animals.

Options: View larger image (or click on image) Download as PowerPoint
The wtTIDM nasal administration suppresses gliosis and inflammation in t...
(A) PS19 mice (7 months old) were given intranasal administration of wtTIDM or mTIDM (0.1 mg/kg) for 1.5 months, and then activation of NF-κB in resident microglia of hippocampus was monitored by double-label immunofluorescence analysis of phospho-p65 in Iba1+ cells. (B) Images were captured at 20× magnification and zoomed to visualize phospho-p65 localization. Expression of phospho-p65 (green) was measured by MFI analysis. (C) Similarly, expression of iNOS in hippocampal microglia was monitored by double immunofluorescence analysis of iNOS and Iba1. Images were captured at 20× magnification. Scale bars: 20 μm. (D) iNOS expression (green) in Iba1+ cells was measured using ImageJ. (E) The number of Iba1+ cells in both the CA1 and DG regions was determined by the manual counting option provided in ImageJ and expressed as cells per mm2 of area. (F) For both MFI and counting analyses, microglia present in both CA1 and DG were considered. Two sections from each brain were included for immunofluorescence analysis, and the value obtained from each section is represented in the bar diagram. The protein level of iNOS as well as Iba1 in hippocampal tissue was also measured by Western blotting, and actin was used the loading control. (G and H) Band densities of iNOS and Iba1 were presented with respect to that of actin. Statistical analyses were performed following 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 (n = 5 different animals).