title: Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice.
abstract: Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia. a.ittner@unsw.edu.au l.ittner@unsw.edu.au.
authors.forename: Arne
authors.initials: A
authors.lastname: Ittner
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Sook Wern
authors.initials: SW
authors.lastname: Chua
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Josefine
authors.initials: J
authors.lastname: Bertz
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Volkerling
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: van der Hoven
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Amadeus
authors.initials: A
authors.lastname: Gladbach
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Przybyla
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Mian
authors.initials: M
authors.lastname: Bi
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.|Motor Neuron Disease Unit, School of Medical Sciences, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Annika
authors.initials: A
authors.lastname: van Hummel
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Stevens
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ippati
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.|Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Suh
authors.affiliation: Biomedical Imaging Facility, Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Macmillan
authors.affiliation: Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Sutherland
authors.affiliation: Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia.
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2050, Australia.
authors.forename: Ana P G
authors.initials: AP
authors.lastname: Silva
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2050, Australia.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.affiliation: Biomedical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Poljak
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.|Transgenic Animal Unit, Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Fabien
authors.initials: F
authors.lastname: Delerue
authors.affiliation: Motor Neuron Disease Unit, School of Medical Sciences, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Yazi D
authors.initials: YD
authors.lastname: Ke
authors.affiliation: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia. a.ittner@unsw.edu.au l.ittner@unsw.edu.au.|Transgenic Animal Unit, Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales 2052, Australia.|Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C558298:Mapt protein, mouse; D008565:Membrane Proteins; D009498:Neurotoxins; D016875:tau Proteins; D048291:Mitogen-Activated Protein Kinase 12; D051528:Guanylate Kinases