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 Article has an altmetric score of 22

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 7

The wtTIDM treatment fails to reduce tau pathology and improve cognitive behavior in PS19 mice lacking TLR2.

Options: View larger image (or click on image) Download as PowerPoint
The wtTIDM treatment fails to reduce tau pathology and improve cognitive...
(A) PS19 mice were bred with TLR2–/– mice to obtain double-transgenic PS19ΔTLR2 mice. These mice were validated by genetic screening, where the 331 bp and 279 bp bands corresponded to nTg and PS19 mice, respectively. Similarly, the 499 bp and 334 bp bands indicate nTg and TLR2–/– mice respectively. PS19ΔTLR2 mice (7 months old) received wtTIDM (0.1 mg/kg/d) nasal administration for 1 month; and at 8.5 months of age, tau pathology in the hippocampus was compared with that of untreated PS19ΔTLR2 and PS19 mice by conducting immunohistochemistry with Tau-5 antibodies. Tau aggregation was monitored in both DG (B) and CA1 (D) neurons. Scale bars: 20 μm (left columns), 10 μm (right columns). (C and E) OD of tau expression was calculated relative to that in nTg mice. Two sections from each brain were used for the staining and quantitative analysis of tau expression, and the values obtained from each section are shown in the bar diagram. Images are shown at 20× and 40× magnifications. Total tau content in sarkosyl-soluble (F) and insoluble fractions (H) was assessed by Western blotting. The tau band densities obtained from the sarkosyl-soluble (G) and -insoluble fractions (I) was normalized to the loading control, actin, present in the soluble fraction. Arrows indicate the different isomers of tau, and the band near 70 kDa obtained from the sarkosyl-soluble fraction was considered for density analysis. Spatial learning and memory were tested by Barnes maze (J, heat map; K, error; L, latency). Statistical analyses were performed using 2-way ANOVA followed by Tukey’s multiple-comparison analysis. **P < 0.01 and ***P < 0.001 compared with the respective groups. Values are presented as mean ± SEM (n = 4 animals per group).