Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease–related mouse models
Debashis Dutta, Malabendu Jana, Ramesh Kumar Paidi, Moumita Majumder, Sumita Raha, Sridevi Dasarathy, Kalipada Pahan
Debashis Dutta, Malabendu Jana, Ramesh Kumar Paidi, Moumita Majumder, Sumita Raha, Sridevi Dasarathy, Kalipada Pahan
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 8

Inflammation induces neuronal tau expression via NF-κB activation.

Options: View larger image (or click on image) Download as PowerPoint
Inflammation induces neuronal tau expression via NF-κB activation. (A) H...
(A) Human SH-SY5Y cells were stimulated with different concentrations of IL-1β under serum-free conditions for 18 hours, then the level of total tau was monitored by Western blotting using Tau-5 antibody. Actin was run as a loading control. (B and C) Tau bands were scanned, and values (B, variant 1/actin; C, variant 2/actin) presented as relative (Rel.) to control. (D) Cells were double-labeled with Tau-5 and NeuN. (E) MFI of tau was measured by NIH ImageJ in 3 images of each of 3 different experiments. (F) After different periods of stimulation with IL-1β, the DNA-binding activity of NF-κB was monitored in nuclear extracts by EMSA. (G) Cells were transfected with PBIIx-Luc for 24 hours, followed by treatment with different concentrations of IL-1β for 4 hours, then luciferase assay in total cell extracts. (H) Map of the WT and mutated NF-κB sites of MAPT promoter luciferase constructs. (I) Cells were transfected with pMAPT(WT)-Luc and pMAPT(mut)-Luc for 24 hours, followed by treatment with IL-1β, and subjected to luciferase assay after 4 hours of stimulation. Cells were treated with IL-1β for 1 hour in serum-free medium, followed by ChIP analysis. Immunoprecipitated chromatin fragments were amplified by semiquantitative (J) and quantitative PCR (K) using primers mentioned in Methods. (L) Cells preincubated with either wtNBD peptide or mNBD peptide for 30 minutes were stimulated by IL-1β for 4 hours, followed by analysis of MAPT mRNAs by quantitative real-time PCR. (M) The schematic diagram showing a detailed map of promoter analysis of the MAPT gene. Results are the mean ± SD of 3 separate experiments. One-way ANOVA followed by Tukey’s multiple-comparison test was used for statistical analyses. *P < 0.05 and ***P < 0.001 versus control.