title: Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration.
abstract: One of the two common hallmark lesions of Alzheimer's disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau,cisp-tau andtransp-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing betweencisandtransisoforms of p-tau (cisp-tau andtransp-tau, respectively),cisp-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robustcisp-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably,cisp-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly,cisp-tau monoclonal antibody treatment not only eliminatescisp-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus,cisp-tau is an early driver of tau pathology in TBI and CTE and detection ofcisp-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of thecisp-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE.
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Onder
authors.initials: O
authors.lastname: Albayram
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Herbert
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Asami
authors.initials: A
authors.lastname: Kondo
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Baxley
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Lian
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Madison
authors.initials: M
authors.lastname: Hansen
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.affiliation: Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA USA.
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu