@misc{oai:repo.qst.go.jp:00073198,
 author = {Higuchi, Makoto and 樋口 真人},
 month = {Jan},
 note = {Accumulations of fibrillary proteins are pathological hallmarks of diverse neurodegenerative disorders, as exemplified by depositions of tau in Alzheimer’s disease (AD) and alpha-synuclein (Asyn) in Parkinson’s disease. These protein aggregates are mechanistically implicated in the disease pathogenesis, providing a rationale for in-vivo imaging of the pathological fibrils to elucidate neurodegenerative mechanisms and to establish disease-specific diagnostic biomarkers. We developed a small-molecule ligand for tau assemblies, PBB3, to capture tau depositions in the living brains. As PBB3 is a self-fluorescent compound, it is applicable to visualization of individual tau inclusions in mouse models by intravital two-photon laser microscopy. Radiolabeled PBB3 can also be utilized for macroscopic positron emission tomography (PET) of tau deposits in animal models and humans. More recently, we have generated a PBB3 derivative, PM-PBB3, which allows detection of tau aggregates with a much higher contrast than PBB3. Notably, clinical PET studies of AD and other tauopathies with PM-PBB3 have indicated that prion-like dissemination of tau fibrillization may involve neural circuits characteristic of each disease type. The application of PBB3 and PM-PBB3 to mouse models has also revealed primary phagocytosis of viable neurons bearing tau inclusions by microglia. Furthermore, structural modifications of PBB3 has led to development of ligands for Asyn deposits, which are currently employed for intravital two-photon microscopy of the mouse brains inoculated with Asyn fibrils. This technology is capable of longitudinally pursuing dissemination of Asyn aggregates through axons, and has demonstrated microglia-mediated loss of neuronal somas and processes involved in the Asyn transmission. Radiolabeled Asyn ligands are presently evaluated by PET imaging of a fibril-inoculated marmoset model, and promising candidates yielding sufficient contrasts will be tested in humans., International Symposium of Brain/MINDS},
 title = {In-vivo multimodal PET and optical imaging of pathological protein depositions in humans and animal models of neurodegenerative disorders},
 year = {2019}
}