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Nature. 2015 Jul 23;523(7561):431-436. doi: 10.1038/nature14658. Epub 2015 Jul 15.

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

Author information

1
Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
2
Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
3
Division of Emergency Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
4
Alzheimer's Disease Center, CTE Program, Boston University School of Medicine, Boston, MA, 02118, USA.
5
Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Harvard Medical School, Boston, MA, 02130.
6
Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan.
8
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
9
Micheli Center for Sports Injury Prevention, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
#
Contributed equally

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.

PMID:
26176913
PMCID:
PMC4718588
DOI:
10.1038/nature14658
[Indexed for MEDLINE]
Free PMC Article

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