Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain

Shuko Takeda, Susanne Wegmann, Hansang Cho, Sarah L. DeVos, Caitlin Commins, Allyson D. Roe, Samantha B. Nicholls, George A. Carlson, Rose Pitstick, Chloe K. Nobuhara, Isabel Costantino, Matthew P. Frosch, Daniel J. Müller, Daniel Irimia and Bradley T. Hyman ()
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Shuko Takeda: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Susanne Wegmann: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Hansang Cho: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School
Sarah L. DeVos: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Caitlin Commins: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Allyson D. Roe: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Samantha B. Nicholls: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
George A. Carlson: McLaughlin Research Institute
Rose Pitstick: McLaughlin Research Institute
Chloe K. Nobuhara: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Isabel Costantino: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Matthew P. Frosch: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School
Daniel J. Müller: Eidgenössische Technische Hochschule Zürich
Daniel Irimia: BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School
Bradley T. Hyman: Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9490

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