Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies

Maiko Ono, Naruhiko Sahara, Katsushi Kumata, Bin Ji, Ruiqing Ni, Shunsuke Koga, Dennis W Dickson, John Q. Trojanowski, Virginia M.Y. Lee, Mari Yoshida, Isao Hozumi, Yasumasa Yoshiyama, John C. van Swieten, Agneta Nordberg, Tetsuya Suhara, Ming Rong Zhang, Makoto Higuchi

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

Original languageEnglish (US)
Pages (from-to)764-780
Number of pages17
JournalBrain : a journal of neurology
Volume140
Issue number3
DOIs
StatePublished - Mar 1 2017

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Tauopathies
Ligands
Progressive Supranuclear Palsy
Protein Isoforms
Diffuse Neurofibrillary Tangles with Calcification
Alzheimer Disease
Brain
Fluorescence
Pick Disease of the Brain
Frontotemporal Dementia
Mutation
Aptitude
Brain Diseases
Neurites
Autoradiography
Fluorescence Microscopy
Neuroglia
Neurodegenerative Diseases
Positron-Emission Tomography
Binding Sites

Keywords

  • Alzheimer’s disease
  • N279K/G272V FTDP-17-MAPT mutation
  • PBB3/AV-1451
  • progressive supranuclear palsy/corticobasal degeneration/Pick’s disease
  • tau PET ligand

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies. / Ono, Maiko; Sahara, Naruhiko; Kumata, Katsushi; Ji, Bin; Ni, Ruiqing; Koga, Shunsuke; Dickson, Dennis W; Trojanowski, John Q.; Lee, Virginia M.Y.; Yoshida, Mari; Hozumi, Isao; Yoshiyama, Yasumasa; van Swieten, John C.; Nordberg, Agneta; Suhara, Tetsuya; Zhang, Ming Rong; Higuchi, Makoto.

In: Brain : a journal of neurology, Vol. 140, No. 3, 01.03.2017, p. 764-780.

Research output: Contribution to journalArticle

Ono, M, Sahara, N, Kumata, K, Ji, B, Ni, R, Koga, S, Dickson, DW, Trojanowski, JQ, Lee, VMY, Yoshida, M, Hozumi, I, Yoshiyama, Y, van Swieten, JC, Nordberg, A, Suhara, T, Zhang, MR & Higuchi, M 2017, 'Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies', Brain : a journal of neurology, vol. 140, no. 3, pp. 764-780. https://doi.org/10.1093/brain/aww339
Ono, Maiko ; Sahara, Naruhiko ; Kumata, Katsushi ; Ji, Bin ; Ni, Ruiqing ; Koga, Shunsuke ; Dickson, Dennis W ; Trojanowski, John Q. ; Lee, Virginia M.Y. ; Yoshida, Mari ; Hozumi, Isao ; Yoshiyama, Yasumasa ; van Swieten, John C. ; Nordberg, Agneta ; Suhara, Tetsuya ; Zhang, Ming Rong ; Higuchi, Makoto. / Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies. In: Brain : a journal of neurology. 2017 ; Vol. 140, No. 3. pp. 764-780.
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AU - Koga, Shunsuke

AU - Dickson, Dennis W

AU - Trojanowski, John Q.

AU - Lee, Virginia M.Y.

AU - Yoshida, Mari

AU - Hozumi, Isao

AU - Yoshiyama, Yasumasa

AU - van Swieten, John C.

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AU - Suhara, Tetsuya

AU - Zhang, Ming Rong

AU - Higuchi, Makoto

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N2 - Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

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