title: Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain.
abstract: Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Shuko
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wegmann
authors.affiliation: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Mechanical Engineering and Engineering Science, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA.
authors.forename: Hansang
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: DeVos
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Commins
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Allyson D
authors.initials: AD
authors.lastname: Roe
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Samantha B
authors.initials: SB
authors.lastname: Nicholls
authors.affiliation: McLaughlin Research Institute, Great Falls, Montana 59405, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.affiliation: McLaughlin Research Institute, Great Falls, Montana 59405, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Chloe K
authors.initials: CK
authors.lastname: Nobuhara
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Costantino
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, 4058 Basel, Switzerland.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Irimia
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002470:Cell Survival; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046210:Microfluidic Analytical Techniques; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins