PT  - JOURNAL ARTICLE
AU  - Hiroyuki Takuwa
AU  - Asumi Orihara
AU  - Yuhei Takado
AU  - Takuya Urushihata
AU  - Masafumi Shimojo
AU  - Ai Ishikawa
AU  - Manami Takahashi
AU  - Anna M. Barron
AU  - Maiko Ono
AU  - Jun Maeda
AU  - Kazuto Masamoto
AU  - Hiroyasu Akatsu
AU  - Aviva M. Tolkovsky
AU  - Bin Ji
AU  - Yutaka Tomita
AU  - Hiroshi Ito
AU  - Ming-Rong Zhang
AU  - Michel Goedert
AU  - Maria Grazia Spillantini
AU  - Virginia M. -Y. Lee
AU  - John Q. Trojanowski
AU  - Taketoshi Maehara
AU  - Tetsuya Suhara
AU  - Naruhiko Sahara
AU  - Makoto Higuchi
TI  - Tracking tau fibrillogenesis and consequent primary phagocytosis of neurons mediated by microglia in a living tauopathy model
AID  - 10.1101/2020.11.04.368977
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.04.368977
4099  - http://biorxiv.org/content/early/2020/11/05/2020.11.04.368977.short
4100  - http://biorxiv.org/content/early/2020/11/05/2020.11.04.368977.full
AB  - Fibrillary tau pathologies have been implicated in Alzheimer’s and allied neurodegenerative diseases, while mechanisms by which neurons bearing tau tangles die remain enigmatic. To address this issue, we pursued tau and related key pathologies macroscopically by PET and MRI and microscopically by intravital two-photon laser optics. Time-course macroscopic assays of tau transgenic mice demonstrated intimate associations of tau deposition and increase of an inflammatory microglial marker, translocator protein (TSPO), with regional brain atrophy. Longitudinal microscopy of these mice revealed a rapid turnover of tau lesions resulting from continuous generation of new tau aggregates followed by loss of neurons and their fibrillar contents. This technology also allowed the capturing of the disappearance of tangle-bearing neurons several days after being engulfed by activated microglia. Notably, a therapeutic TSPO ligand profoundly suppressed the mobility and phagocytotic activity of microglia and improved neuronal survival in this model, supporting the involvement of primary phagocytosis of viable neurons by microglia in tau-primed neuronal death. Finally, partial depletion of microglia revealed roles of immune factors, MFG-E8 and C1q, as ‘eat-me’ signals for an immediate attraction of phagocytic microglia towards the elimination of tangle-loaded neurons.Competing Interest StatementThe authors have declared no competing interest.