Presentation In vivo brain imaging for studying possible linkage between pathological hallmark of tauopathy and neuronal loss

Takuwa, Hiroyuki  ,  Urushihata, Takuya  ,  Minamihisamatsu, Takeharu  ,  Tokunaga, Masaki  ,  Shimojo, Masafumi  ,  Matsumoto, Izumi  ,  Ming-Rong, Zhang  ,  Suhara, Tetsuya  ,  Higuchi, Makoto  ,  Sahara, Naruhiko

Accumulation of intracellular neurofibrillary tangles (NFTs) consisting of microtubule-associated protein tau is a major hallmark of tauopathy. Recently, a PBB3 ligand that selectively binding to tau inclusions was developed for the diagnosis of tauopathy. This ligand is useful for both positron emission tomography (PET) imaging and fluorescence imaging. Taking advantage of this multimodality of the PBB3 ligand, in vivo monitoring of NFT formation has been examined using tauopathy mouse model rTg4510 mice. This model typically exhibits forebrain atrophy and intraneuronal tau accumulation by 6 months of age. In this study, we performed in vivo two-photon microscopic imaging to investigate the progression of tau pathology at the cellular level. Fixation of a chronic cranial window to the skull enabled longitudinal monitoring for two months. In parallel, volumetric magnetic resonance imaging and [11C]PBB3-PET were conducted for the diagnoses of neurodegeneration. PBB3-positive inclusions were visualized with two-photon imaging as early as 4 months of age, while forebrain atrophy and [11C]PBB3 signal became noticeable at 6 months of age. The PBB3 signals from both PET and two-photon imaging reached a plateau at 6 months of age. Interestingly, although two-photon imaging revealed that PBB3-positive inclusions were continuously produced, subpopulations of the PBB3-positive inclusions disappeared within a few weeks. These results suggest that there is a rapid turnover of PBB3-positive inclusions. The rates of generation and disappearance were significantly reduced by the suppression of human P301L tau indicating that regulating human P301L tau expression enables the turnover to be controlled. In addition, disappearance rate of neurons with PBB3-positive inclusions was higher that that of neurons without PBB3-positive inclusions. These results suggest a strong association between PBB3-positive tau inclusions and neuronal death. In vivo multiscale imaging techniques could be useful tools to elucidate mechanisms of tau-induced neurotoxicity and to develop therapeutic interventions in tauopathy.
Berlin BRAIN & BRAIN PET 2017

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