Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice
Authors: Yazi D Ke
Alexander Macmillan
Josefine Bertz
Anne Poljak
Greg Sutherland
Ana P G Silva
Claire H Stevens
Fabien Delerue
Annika van Hummel
Magdalena Przybyla
Stefania Ippati
Amadeus Gladbach
Lars M Ittner
Mian Bi
Arne Ittner
Joel P Mackay
Alexander Volkerling
Lisa S Suh
Jillian J Kril
Julia van der Hoven
Sook Wern Chua
Journal: Science (2016)
Discipline: Multidisciplinary
Keywords: Amyloid-β; Alzheimer's disease; tau phosphorylation; p38 mitogen-activated protein kinase; excitotoxicity
Affiliations: Dementia Research Unit, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales 2052, Australia.  ., 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., Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia., Biomedical Imaging Facility, Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales 2052, Australia., School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2050, Australia., Biomedical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales 2052, Australia., Transgenic Animal Unit, Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales 2052, Australia., Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.

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. 

Retracted: No

PubPeer comments:
 This paper appears to have a classic logical flaw commonly found in many biomedical literatures. To determine whether Tau is ***required*** for p38gamma-mediated inhibition of Abeta toxicity, the authors used Tau knockout mice. Getting negative data from Tau knockout mice, but positive data from Tau wild-type mice, do not necessarily mean that Tau is required. When the Tau gene was deleted, the baseline data are also changed. For example, in Figure 2A, the deletion of Tau in p38gamma wild-type mice already protected mice from an early death. Therefore, getting negative data from p38gamma knockout on Tau knockout mice is meaningless. Getting negative data from p38gamma knockout on Tau knockout mice is meaningful ***only if*** Tau knockout on p38gamma wild-type mice had the same mortality as Tau Wild-type on p38gamma wild-type mice. ,