Spatial Transcriptomics analysis of transgenic mice (Alzheimer´s disease) reveal dysregulation of Ttr.. Spatial transcriptomics reveals an unexpected impact of tau and tau pathology on the expression of transthyretin

Gene expression changes contribute to neurodegenerative diseases including tauopathies. Tau is a multifunctional protein which is involved in the regulation of gene expression. We have used two mouse models, THY-Tau22 mice, which express a pro-aggregation form of tau, and KOTau mice, which are null for tau, to improve our understanding of how tau alters gene expression in the brain. Spatial transcriptomics was used to interrogate regional expression changes. Among a set of genes encoding for chaperones, we identified the transthyretin gene Ttr as being dysregulated in a tau-dependent manner. Immunofluorescence (IF) revealed increased TTR protein expression in THY-Tau22 mice and lowered expression in KOTau mice in the choroid plexus epithelial cells, which are important for CSFfluid composition. As TTR is involved in the clearance of Aβ and the prevention of Aβ aggregation, we evaluated endogenous mouse Aβ in the hippocampus from KOTau mice and observed increased Aβ deposits. Our study reveals a hitherto unknown regulatory role of tau on Ttr gene and protein expression which may contribute to a feedback loop contributing to Aβ disease progression.