title: Analysis of tau post-translational modifications in rTg4510 mice, a model of tau pathology.
abstract: BACKGROUND
  Microtubule associated protein tau is the major component of the neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer's disease and several other neurodegenerative diseases. Tau mutations are associated with frontotemperal dementia with parkinsonism on chromosome 17 (FTDP-17). rTg4510 mice overexpress human tau carrying the P301L FTDP-17 mutation and develop robust NFT-like pathology at 4-5 months of age. The current study is aimed at characterizing the rTg4510 mice to better understand the genesis of tau pathology and to better enable the use of this model in drug discovery efforts targeting tau pathology.
  
  
  RESULTS
  Using a panel of immunoassays, we analyzed the age-dependent formation of pathological tau in rTg4510 mice and our data revealed a steady age-dependent accumulation of pathological tau in the insoluble fraction of brain homogenates. The pathological tau was associated with multiple post-translational modifications including aggregation, phosphorylation at a wide variety of sites, acetylation, ubiquitination and nitration. The change of most tau species reached statistical significance at the age of 16 weeks. There was a strong correlation between the different post-translationally modified tau species in this heterogeneous pool of pathological tau. Total tau in the cerebrospinal fluid (CSF) displayed a multiphasic temporal profile distinct from the steady accumulation of pathological tau in the brain. Female rTg4510 mice displayed significantly more aggressive accumulation of pathological tau in the brain and elevation of total tau in CSF than their male littermates.
  
  
  CONCLUSIONS
  The immunoassays described here were used to generate the most comprehensive description of the changes in various tau species across the lifespan of the rTg4510 mouse model. The data indicate that development of tauopathy in rTg4510 mice involves the accumulation of a pool of pathological tau that carries multiple post-translational modifications, a process that can be detected well before the histological detection of NFTs. Therapeutic treatment targeting tau should therefore aim to reduce all tau species associated with the pathological tau pool rather than reduce specific post-translational modifications. There is still much to learn about CSF tau in physiological and pathological processes in order to use it as a translational biomarker in drug discovery.
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. Lsong2008@gmail.com.|Current address: BioDuro, a PPD Company, Beijing, China. Lsong2008@gmail.com.
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. Sherry.lu@merck.com.
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Lu
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. ouyang_xs@hotmail.com.|Current address: Medical Oncology Department, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. ouyang_xs@hotmail.com.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Molecular Biomarkers, Merck Research Laboratories, Kenilworth, NJ, USA. jmelchor@gmail.com.|Current address: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. jmelchor@gmail.com.
authors.forename: Jerry
authors.initials: J
authors.lastname: Melchor
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. Julie.lee@merck.com.
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. Giuseppe.terracina@merck.com.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terracina
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, PA, USA. Xiaohai_wang@merck.com.
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. Lynn.hyde@merck.com.
authors.forename: Lynn
authors.initials: L
authors.lastname: Hyde
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. hessf@comcast.net.
authors.forename: J Fred
authors.initials: JF
authors.lastname: Hess
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. eric.parker@merck.com.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ, USA. llzh@icloud.com.|Current address: Department of Neuroscience, Novartis Institute for Biomedical Research, Cambridge, MA, USA. llzh@icloud.com.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational / Q000235:genetics* / Q000502:physiology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016875:tau Proteins