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A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model

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Abstract

Purpose

Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimer’s disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies.

Methods

A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer, 18F-PM-PBB3, and MRI at various ages (1.8–12.3 months). Using the cerebellum as reference, the radiotracer binding in target regions was estimated as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR). Histopathological staining of brain sections derived from scanned animals was also conducted to investigate the imaging-neuropathology correlations.

Results

18F-PM-PBB3 SUVR at 40–60 min in the neocortex, hippocampus, and striatum of rTg4510 mice agreed with DVR, became significantly different from control values around 4–5 months of age, and progressively and negatively correlated with age and local volumes, respectively. Neocortical SUVR also correlated with the abundance of tau inclusions labeled with PM-PBB3 fluorescence, Gallyas-Braak silver impregnation, and anti-phospho-tau antibodies in postmortem assays. The in vivo and ex vivo 18F-PM-PBB3 binding was blocked by non-radioactive PM-PBB3. 18F-PM-PBB3 yielded a 1.6-fold greater dynamic range for tau imaging than its ancestor, 11C-PBB3.

Conclusion

Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.

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Data availability

PM-PBB3 and its radiolabeling precursor will be made available upon request. As we granted license on PM-PBB3 and related materials to APRINOIA Therapeutics Inc., material transfer will be subjected to a sublicense agreement with this company if there is potential for commercial application.

Code availability

The datasets supporting the current study have not been deposited in a public repository but are available from the lead contact upon reasonable request.

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Acknowledgements

The authors thank Jun Maeda at the National Institutes for Quantum Science and Technology for critical discussions, and Masaki Tokunaga, Nobuhiro Nitta, Sayaka Shibata, Takeharu Minamihisamatsu, Kana Osawa, Shoko Uchida, and Sayuri Sasaki at the National Institutes for Quantum Science and Technology for technical assistance. The authors are grateful to the staff of the Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, for their technical assistance in radiopharmaceuticals production.

Funding

This study was supported in part by AMED under Grant Number JP19dk0207049, JP22dk0207063, JP21dm0207072, and JP21dk0207046, by JST Grant Number JPMJCR1652 and JPMJMS2024, and by MEXT/JSPS KAKENHI Grant Number JP16H05324, JP19K08005, JP17J06398, and JP17K07113.

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Author notes

  1. Taeko Kimura and Maiko Ono contributed equally to this work.

    Taeko Kimura currently belongs to Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.

Authors and Affiliations

  1. National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan

    Taeko Kimura, Maiko Ono, Chie Seki, Kazuaki Sampei, Masafumi Shimojo, Kazunori Kawamura, Ming-Rong Zhang, Naruhiko Sahara, Yuhei Takado & Makoto Higuchi

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  1. Taeko Kimura
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Taeko Kimura, Maiko Ono, Chie Seki, Kazuaki Sampei, Masafumi Shimojo, and Yuhei Takado. The first draft of the manuscript was written by Taeko Kimura, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chie Seki or Yuhei Takado.

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Ethics approval

Protocols for the present animal experiments were approved by the Animal Ethics Committees of the National Institutes for Quantum Science and Technology (approval number: 07-1049-31).

Conflict of interest

M.-R.Z. and M.H. hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672).

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Kimura, T., Ono, M., Seki, C. et al. A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model. Eur J Nucl Med Mol Imaging 49, 4298–4311 (2022). https://doi.org/10.1007/s00259-022-05898-3

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