Spatial transcriptomics reveals an unexpected impact of tau and tau pathology on the expression of transthyretin

TL;DR

This study shows that tau protein affects the expression of transthyretin (Ttr), a protein linked to Alzheimer's disease, in mouse brain regions.

Contribution

The study reveals a novel regulatory role of tau in modulating Ttr expression, potentially influencing Aβ pathology in Alzheimer's disease.

Findings

Transthyretin (Ttr) mRNA is dysregulated in a tau-dependent manner in mouse brain regions.

TTR protein levels are increased in THY-Tau22 mice and decreased in TauKO mice in choroid plexus epithelial cells.

Tau deficiency leads to increased Aβ deposits, suggesting a role for Ttr in Aβ clearance and disease progression.

Abstract

RNA expression is modulated by tau. We used two mouse models, THY-Tau22 mice, which express pro-aggregation tau, and TauKO mice, which are null for tau, to improve our understanding of tau-altered mRNA expression in brain.

Spatial transcriptomics on Tau22 and TauKO mice were used to interrogate regional mRNA expression changes. We focused on mRNA expression changes in the hippocampus and ventricles; two regions altered early in Alzheimer’s disease.

We identified the transthyretin mRNA, Ttr, as being dysregulated in a tau-dependent manner. Immunofluorescence (IF) revealed increased TTR protein expression in THY-Tau22 mice and lowered expression in TauKO mice in the choroid plexus epithelial cells.

As TTR is involved in the clearance of Aβ and the prevention of Aβ aggregation, we evaluated endogenous mouse Aβ in TauKO mice and observed increased Aβ deposits. Our study reveals a hitherto unknown regulatory role of tau on Ttr mRNA and protein expression, which may participate in a feedback loop contributing to Aβ disease progression.

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