title: Human secreted tau increases amyloid-beta production.
abstract: The interaction of amyloid-beta (Aβ) and tau in the pathogenesis of Alzheimer's disease is a subject of intense inquiry, with the bulk of evidence indicating that changes in tau are downstream of Aβ. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases Aβ plaque deposition. Here, we confirm that human tau increases Aβ levels. To determine if the observed changes in Aβ levels were because of intracellular or extracellular secreted tau (eTau for extracellular tau), we affinity purified secreted tau from Alzheimer's disease patient-derived cortical neuron conditioned media and analyzed it by liquid chromatography-mass spectrometry. We found the extracellular species to be composed predominantly of a series of N-terminal fragments of tau, with no evidence of C-terminal tau fragments. We characterized a subset of high affinity tau antibodies, each capable of engaging and neutralizing eTau. We found that neutralizing eTau reduces Aβ levels in vitro in primary human cortical neurons where exogenously adding eTau increases Aβ levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced Aβ levels. We show that the human tau insert sequence is sufficient to cause the observed increase in Aβ levels. Our data furthermore suggest that neuronal hyperactivity may be the mechanism by which this regulation occurs. We show that neuronal hyperactivity regulates both eTau secretion and Aβ production. Electrophysiological analysis shows for the first time that secreted eTau causes neuronal hyperactivity. Its induction of hyperactivity may be the mechanism by which eTau regulates Aβ production. Together with previous findings, these data posit a novel connection between tau and Aβ, suggesting a dynamic mechanism of positive feed forward regulation. Aβ drives the disease pathway through tau, with eTau further increasing Aβ levels, perpetuating a destructive cycle.
authors.affiliation: Department of Discovery Biology, iPierian, South San Francisco, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bright
authors.affiliation: Department of Translational Research, iPierian, South San Francisco, CA, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Discovery Biology, iPierian, South San Francisco, CA, USA.
authors.forename: Vu
authors.initials: V
authors.lastname: Dang
authors.affiliation: Department of Discovery Biology, iPierian, South San Francisco, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wright
authors.affiliation: Department of Discovery Biology, iPierian, South San Francisco, CA, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Cooper
authors.affiliation: Department of Translational Research, iPierian, South San Francisco, CA, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Byun
authors.affiliation: Department of Translational Research, iPierian, South San Francisco, CA, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Ramos
authors.affiliation: Department of Translational Research, iPierian, South San Francisco, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Translational Research, iPierian, South San Francisco, CA, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Parry
authors.affiliation: Department of Discovery Biology, iPierian, South San Francisco, CA, USA; Department of Translational Research, iPierian, South San Francisco, CA, USA. Electronic address: nancy.stagliano@ipierian.com.
authors.forename: Nancy
authors.initials: N
authors.lastname: Stagliano
authors.affiliation: Department of Discovery Biology, iPierian, South San Francisco, CA, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Griswold-Prenner
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002853:Chromatography, Liquid; D006801:Humans; D013058:Mass Spectrometry; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D016875:tau Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins
keywords: Alzheimer's disease; Amyloid-beta (Aβ); Extracellular tau; Feed forward mechanism; Neuronal hyperactivity; Secreted tau; eTau; sAPPα