In vivo positron emission tomographic imaging of glial responses to amyloid-β and tau pathologies in mouse models of Alzheimer's disease and related disorders

Jun Maeda, Ming Rong Zhang, Takashi Okauchi, Bin Ji, Maiko Ono, Satoko Hattori, Katsushi Kumata, Nobuhisa Iwata, Takaomi C. Saido, John Q. Trojanowski, Virginia M.Y. Lee, Matthias Staufenbiel, Takami Tomiyama, Hiroshi Mori, Toshimitsu Fukumura, Tetsuya Suhara, Makoto Higuchi

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Abstract

Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [ 11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compound-B, to plaques. In these animals, [ 11C]AC-5216 yielded better TSPO contrasts than [18F] fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance. TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.

Original languageEnglish
Pages (from-to)4720-4730
Number of pages11
JournalJournal of Neuroscience
Volume31
Issue number12
DOIs
Publication statusPublished - 23-03-2011

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Maeda, J., Zhang, M. R., Okauchi, T., Ji, B., Ono, M., Hattori, S., Kumata, K., Iwata, N., Saido, T. C., Trojanowski, J. Q., Lee, V. M. Y., Staufenbiel, M., Tomiyama, T., Mori, H., Fukumura, T., Suhara, T., & Higuchi, M. (2011). In vivo positron emission tomographic imaging of glial responses to amyloid-β and tau pathologies in mouse models of Alzheimer's disease and related disorders. Journal of Neuroscience, 31(12), 4720-4730. https://doi.org/10.1523/JNEUROSCI.3076-10.2011