Modulation of the Inflammatory Response by the RNA-binding protein TIA1 in the P301S Mouse Model of Tauopathy

Identification: LeBlang, Chelsey


Description

 

Modulation of the Inflammatory Response by the RNA-binding protein TIA1 in the P301S Mouse Model of Tauopathy
 
Chelsey J. LeBlang1*, Benjamin Wolozin2, Jennifer Luebke1
1Department of Anatomy & Neurobiology, and 2Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine
      
Tauopathies such as Alzheimer's Disease and Frontotemporal Dementia are characterized by aggregation of hyperphosphorylated tau protein, widespread neuro-inflammation and neuronal death. We have recently shown that the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity in part through the binding of phospho-tau oligomers into pathological stress granules (Vanderweyde et al., 2016; Apicco et al., 2017). Haplo-insufficiency of TIA1 in the P301S mouse model of tauopathy reduced the accumulation of tau oligomers, as well as the development of downstream cognitive deficits, cortical thinning, and synapse loss. In the healthy brain TIA1 acts as a regulator of the innate immune response and of cell death by binding and sequestering TNFα and COX2 mRNA transcripts into normal stress granules (Ash et al., 2014; Lopez de Silanes et al., 2005). The putative role of TIA1 in the immune response led us to hypothesize that TIA1 reduction might impact on the immune system in mice subjected to tauopathy, Here, we characterized the inflammatory response in P301S vs. WT mice that were TIA1+/+, TIA1+/- or TIA1 -/-. We observed that TIA1 reduction was associated with a striking increase in inflammation. Immunohistochemistry and stereologic counting techniques were used to assess microglial morphology and MHCII antigen presentation in the CA1 and Dentate Gyrus regions of the dorsal hippocampus. In all P301S groups, microglial activation was significantly greater compared to WT, confirming that tauopathy induces neuro-inflammation in this model. There was also a significantly higher number of activated microglia in the P301S TIA1 -/- compared to P301S TIA+/+ and P301S TIA+/-, which did not differ. The inflammatory response was not observed in the WT TIA1 -/- group, indicating that the phenotype seen in the P301S TIA-/- group requires the presence of tau and/or downstream neuropathological insults. Finally, gross atrophy of the hippocampus was observed in P301S TIA1 -/- mice but not in the other genotypic groups.  These results suggest an important role of TIA1 as a regulator of neuro-inflammation in the context of tauopathy.
 
Supported by NIH AG050471
 

 

Credits

Credits: None available.

You must be logged in and own this product in order to post comments.