Abstract

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.

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Acknowledgements

We thank T. Hunter and M. Zeidel for advice; S. Hagen for Microscopy Facility (NIH grant S10 RR017927) and P. Davies for tauopathy antibodies. C.-H.C., Y.-M.L., J.A.D. and S.W. are recipients of NIA-funded T32 Translational Research in Aging Training Grant, National Science Council Postdoctoral Fellowship from Taiwan, a VA Career Development Award, and Susan G. Komen postdoctoral fellowship, respectively. R.M. is supported by Boston Children’s Hospital Pilot Grant Award and NIH training grant T32HD040128, and A.P.-L. and W.M. by NFLPA. The CTE and blast samples used are supported by grants from NIH (UO1NS086659-01, P30AG13846), VA, Sports Legacy Institute, Andlinger Foundation, NFL and WWE. The work is supported by NIH grants R01AG029385, R01CA167677, R01HL111430 and R01AG046319, and Alzheimer's Association grant DVT-14-322623 to K.P.L. and BIDMC and NFLPA pilot grants to K.P.L. and X.Z.Z.

Author information

Author notes

    • Asami Kondo
    •  & Koorosh Shahpasand

    These authors contributed equally to this work.

    • Xiao Zhen Zhou
    •  & Kun Ping Lu

    These authors jointly supervised this work.

Affiliations

  1. Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Asami Kondo
    • , Koorosh Shahpasand
    • , Chun-Hau Chen
    • , Yandan Yao
    • , Yu-Min Lin
    • , Jane A. Driver
    • , Shuo Wei
    • , Man-Li Luo
    • , Onder Albayram
    • , Pengyu Huang
    • , Xiao Zhen Zhou
    •  & Kun Ping Lu
  2. Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Asami Kondo
    • , Koorosh Shahpasand
    • , Chun-Hau Chen
    • , Yandan Yao
    • , Yu-Min Lin
    • , Shuo Wei
    • , Man-Li Luo
    • , Onder Albayram
    • , Pengyu Huang
    • , Xiao Zhen Zhou
    •  & Kun Ping Lu
  3. Division of Emergency Medicine, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Rebekah Mannix
    •  & Jianhua Qiu
  4. Alzheimer’s Disease Center, CTE Program, Boston University School of Medicine, Boston, Massachusetts 02118, USA

    • Juliet Moncaster
    • , Lee E. Goldstein
    •  & Ann C. McKee
  5. Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02130, USA

    • Jane A. Driver
  6. Department of Neurology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Yan Sun
    •  & Alexander Rotenberg
  7. Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan

    • Akihide Ryo
  8. Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Alvaro Pascual-Leone
  9. Micheli Center for Sports Injury Prevention, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA

    • William Meehan

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Contributions

A.K. and K.S. designed the studies, performed the experiments, and wrote the manuscript; R.M. helped design and conduct experiments and analysed the data on impact TBI mouse models and wrote the manuscript; J.Q. and W.M. helped with impact TBI experiments, J.M. and L.E.G. helped with blast TBI experiments and edited the manuscript; A.C.M. provided human brains and edited the manuscript; Y.S. and A.Ro. performed field excitatory postsynaptic potential (fSPSP) recording; C.-H.C., Y.Y., Y.-M.L, J.A.D., S.W., M.-L.L., O.A. and P.H. provided technical assistance; A.Ry. provided assistance for developing mAbs; A.P.-L. advised the project; X.Z.Z. originally discovered the procedures for generating cis and trans antibodies; and X.Z.Z. and K.P.L. conceived and supervised the project, designed the studies, analysed the data, and wrote the manuscript.

Competing interests

Competing Financial Interests. K.P.L. and X.Z.Z. are inventors of Pin1 technology, which was licensed by Beth Israel Deaconess Medical Center to Pinteon Therapeutics. Both K.P.L. and X.Z.Z. own equity in, and consult for, Pinteon. K.P.L. also serves on its Board of Directors. Their interests were reviewed and are managed by Beth Israel Deaconess Medical Center in accordance with its conflict of interest policy.

Corresponding authors

Correspondence to Xiao Zhen Zhou or Kun Ping Lu.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Table 1 and Source Data images.

Videos

  1. 1.

    Mitochondrial movement in control PC12 cells

    Differentiated PC12 cells under normal condition were stained with MitoTracker Green FM and subjected for live-cell confocal imaging captured fast and slow transport of mitochondria (green dots) in the anterograde and retrograde directions along neurites.

  2. 2.

    Hypoxia stops fast, but not slow mitochondrial movement in PC12 cells.

    Differentiated PC12 cells cultured in a hypoxia chamber were stained with MitoTracker Green FM and subjected for live-cell confocal imaging. Hypoxia treatment, however, almost completely stopped fast transport of mitochondria (green dots) in both directions, without obvious effects on slow mitochondrial movement in the same neurites.

  3. 3.

    cis mAb rescues defective fast mitochondrial movement induced by hypoxia in PC12 cells

    Differentiated PC12 cells cultured in a hypoxia chamber in the presence of cis mAb were stained with MitoTracker Green FM and subjected for live-cell confocal imaging. cis mAb treatment restored the defective transport of mitochondria (green dots) in both anterograde and retrograde directions along neurites.

  4. 4.

    trans mAb even accelerates retraction of entire neurites induced by hypoxia in PC12 cells

    Differentiated PC12 cells cultured in a hypoxia chamber in the presence of trans mAb were stained with MitoTracker Green FM and subjected for live-cell confocal imaging. trans mAb treatment even accelerated retraction of entire neurites.

  5. 5.

    Overexpression of tau and p25/Cdk5 causes neuronal death

    HS-SY5Y cells were cotransfected with GFP-tau and p25/Cdk5 and subjected for live-cell imaging with confocal microscopy. GFP-tau-overexpressing cells (green) died after around 62 hr of transfection while the untransfected cells (phase) remain survive over the observation time.

  6. 6.

    cis mAb rescues neuronal death induced by overexpression of tau and p25/Cdk5

    HS-SY5Y cells were cotransfected with GFP-tau and p25/Cdk5 and treated with cis mAb and subjected for live-cell imaging with confocal microscopy. cis mAb treatment blocked cell death caused by GFP-tau+p25/Cdk5 overexpression. Both transfected (green) and untransfected cells (phase) survived over the observation time.

  7. 7.

    Sham mice stayed mainly in the two closed or “safe” arms in the elevated plus maze

    Sham mice were subjected to the elevated plus maze 2 months after injury. The mice were placed at the decision zone and they could enter any of these four arms within 5-minute period of test time. A video-tracking system was used to record the move of the mice. Sham mice largely stayed in the two closed or “safe” arms, exhibiting minimal risk-taking behavior.

  8. 8.

    IgG-treated ssTBI mice explore the two open or “aversive” arms, displaying “risk-taking” behavior in the elevated plus maze

    ssTBI mice were subjected to the elevated plus maze 2 months after IgG treatment. The mice were placed at the decision zone and they could enter any of these four arms within 5-minute period of test time. A video-tracking system was used to record the move of the mice. IgG-treated ssTBI mice strikingly explored the two open or “aversive” arms, displaying “risk-taking” behavior.

  9. 9.

    cis mAb-treated ssTBI mice stayed mainly in the two closed or “safe” arms in the elevated plus maze

    ssTBI mice were subjected to the elevated plus maze 2 months after cis mAb treatment. The mice were placed at the decision zone and they could enter any of these four arms within 5-minute period of test time. A video-tracking system was used to record the move of the mice. cis mAb-treated mice largely stayed in the two closed or “safe” arms, exhibiting minimal risk-taking behavior, similar to sham mice.

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https://doi.org/10.1038/nature14658

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