title: Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients.
abstract: Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high-molecular-weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates.
  
  
  
  We have examined seeding and uptake properties of brain extracellular tau from various sources, including interstitial fluid (ISF) and CSF from an AD transgenic mouse model and postmortem ventricular and antemortem lumbar CSF from AD patients.
  
  
  
  We found that brain ISF and CSF tau from the AD mouse model can be taken up by cells and induce intracellular aggregates. Ventricular CSF from AD patients contained a rare HMW tau species that exerted a higher seeding activity. Notably, the HMW tau species was also detected in lumbar CSF from AD patients, and its levels were significantly elevated compared to control subjects. HMW tau derived from CSF of AD patients was seed competent in vitro.
  
  
  
  These findings suggest that CSF from an AD brain contains potentially bioactive HMW tau species, giving new insights into the role of CSF tau and biomarker development for AD. Ann Neurol 2016;80:355-367.
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA. takeda@cgt.med.osaka-u.ac.jp.
authors.forename: Shuko
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Commins
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: DeVos
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Chloe K
authors.initials: CK
authors.lastname: Nobuhara
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wegmann
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Allyson D
authors.initials: AD
authors.lastname: Roe
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Costantino
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Samantha B
authors.initials: SB
authors.lastname: Nicholls
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Alexis E
authors.initials: AE
authors.lastname: Sherman
authors.affiliation: Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital, Boston, MA.
authors.forename: Ana T
authors.initials: AT
authors.lastname: Trisini Lipsanopoulos
authors.affiliation: Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA.
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
authors.affiliation: McLaughlin Research Institute, Great Falls, MT.
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.affiliation: McLaughlin Research Institute, Great Falls, MT.
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA.|Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA.|Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA.
authors.forename: Murray A
authors.initials: MA
authors.lastname: Raskind
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA.|Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA.
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D015415:Biomarkers; D016875:tau Proteins