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

Deborah L Croteau^1,2*Jose Fernandez Navarro³thomas comptdaer⁴Zaneta Andrusivova³Aleksandra Jurek³Eliette Bonnefoy^4,5Luc Buee⁴Vilhelm Bohr^6,7Joakim Lundeberg³Marie-Christine Galas⁴

• ¹National Institute on Aging, Laboratory of Genomics and Genetics, Computational Biology and Genomic Core, Baltimore, United States
• ²National Institute on Aging, Section on DNA Repair, 251 Bayview Blvd, Ste 100, Baltimore, Maryland, United States
• ³Science for Life Laboratory, Division of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
• ⁴4Univ. Lille, Inserm, CHU Lille, CNRS, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France
• ⁵Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France
• ⁶Dept of ICMM, University of Copenhagen, Copenhagen, Denmark
• ⁷Section on DNA Repair, National Institute on Aging Intramural Research Program, Baltimore, United States

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 were used to interrogate regional expression changes. Focusing on 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.