A novel tauopathy model mimicking molecular and spatial aspects of human tau pathology.

Creating a mouse model that recapitulates human tau pathology is essential for developing strategies to intervene in tau-induced neurodegeneration. However, mimicking the pathological features seen in human pathology often involves a trade-off with artificial effects such as unexpected gene insertion and neurotoxicity from the expression system. To overcome these issues, we developed the rTKhomo mouse model by combining a transgenic CaMKII-tTA system with a P301L mutated 1N4R human tau knock-in at the Rosa26 locus with a C57BL/6J background. This model closely mimics human tau pathology, particularly in the hippocampal CA1 region, showing age-dependent tau accumulation, neuronal loss and neuroinflammation. Notably, whole-brain 3D staining and light-sheet microscopy revealed a spatial gradient of tau deposition from the entorhinal cortex to the hippocampus, similar to the spatial distribution of Braak neurofibrillary tangle staging. Furthermore, [ ¹⁸ F]PM-PBB3 positron emission tomography imaging enabled the quantification and live monitoring of tau deposition. The rTKhomo mouse model shows potential as a promising next-generation preclinical tool for exploring the mechanisms of tauopathy and for developing interventions targeting the spatial progression of tau pathology.
Competing Interests: M.H. hold patents on compound related to the present report (JP5422782/EP12884742.3/CA2894994/HK1208672). H.R.U. is a founder of CUBICStars, Inc. that offers services based on CUBIC technology. E.A.S. is employed by the company. E.A.S. and H.R.U. are co-inventors on patents and patent applications owned by RIKEN and CUBICStars, Inc., covering the CUBIC reagents and CUBIC-HV kits, respectively.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)