Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy

Asami Kondo, Koorosh Shahpasand, Rebekah Mannix, Jianhua Qiu, Juliet Moncaster, Chun-Hau Chen, Yandan Yao, Yu-Min Lin, Jane A. Driver, Yan Sun, Shuo Wei, Man-Li Luo, Onder Albayram, Pengyu Huang, Alexander Rotenberg, Akihide Ryo, Lee E. Goldstein, Alvaro Pascual-Leone, Ann C. McKee, William Meehan, Xiao Zhen Zhou () and Kun Ping Lu ()
Additional contact information
Asami Kondo: Beth Israel Deaconess Medical Center, Harvard Medical School
Koorosh Shahpasand: Beth Israel Deaconess Medical Center, Harvard Medical School
Rebekah Mannix: Children’s Hospital Boston, Harvard Medical School
Jianhua Qiu: Children’s Hospital Boston, Harvard Medical School
Juliet Moncaster: Alzheimer’s Disease Center, CTE Program, Boston University School of Medicine
Chun-Hau Chen: Beth Israel Deaconess Medical Center, Harvard Medical School
Yandan Yao: Beth Israel Deaconess Medical Center, Harvard Medical School
Yu-Min Lin: Beth Israel Deaconess Medical Center, Harvard Medical School
Jane A. Driver: Beth Israel Deaconess Medical Center, Harvard Medical School
Yan Sun: Children’s Hospital Boston, Harvard Medical School
Shuo Wei: Beth Israel Deaconess Medical Center, Harvard Medical School
Man-Li Luo: Beth Israel Deaconess Medical Center, Harvard Medical School
Onder Albayram: Beth Israel Deaconess Medical Center, Harvard Medical School
Pengyu Huang: Beth Israel Deaconess Medical Center, Harvard Medical School
Alexander Rotenberg: Children’s Hospital Boston, Harvard Medical School
Akihide Ryo: Yokohama City University School of Medicine
Lee E. Goldstein: Alzheimer’s Disease Center, CTE Program, Boston University School of Medicine
Alvaro Pascual-Leone: Beth Israel Deaconess Medical Center, Harvard Medical School
Ann C. McKee: Alzheimer’s Disease Center, CTE Program, Boston University School of Medicine
William Meehan: Micheli Center for Sports Injury Prevention, Children’s Hospital Boston, Harvard Medical School
Xiao Zhen Zhou: Beth Israel Deaconess Medical Center, Harvard Medical School
Kun Ping Lu: Beth Israel Deaconess Medical Center, Harvard Medical School

Nature, 2015, vol. 523, issue 7561, 431-436

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14658

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