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Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ

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Abstract

Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer’s disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two Aβ-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic Aβ-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer’s mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human Aβ. Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.

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Acknowledgements

The authors would like to thank staff of Macquarie Animal Research Services (MARS), Troy Butler and Jess Spathos for help with animal husbandry.

Funding

This work was supported by funding from the National Health and Medical Research Council (Grant# 1081916, 1123564, 1132524, 1136241, 1143848, 1143978, 1176628), the Australian Research Council (Grant# DP170100781, DP170100843, DP200102396) and Macquarie University. AI is a National Health and Medical Research Council Emerging Leadership fellow (Grant# 1176628).

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  1. Arne Ittner and Lars M. Ittner contributed equally to this work.

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  1. Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia

    Arne Ittner, Prita Riana Asih, Amanda R. P. Tan, Emmanuel Prikas, Josefine Bertz, Kristie Stefanoska, Yijun Lin, Alexander M. Volkerling, Yazi D. Ke, Fabien Delerue & Lars M. Ittner

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Contributions

AI and LMI conceived of the original study concept, designed over-arching research strategy and co-led the study. AI designed the specific research plan of all experiments. AI, PRA, EP and KS performed experiments, analyzed data and prepared figures. AI, KS, PRA, ARPT and JB performed behavior tests and analyzed data. YL and AMV provided critical assistance with experiments. AI, YDK and LMI obtained funding. AI and LMI supervised experiments. All authors contributed to writing of the manuscript.

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Correspondence to Arne Ittner or Lars M. Ittner.

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Conflict of interest

AI and LMI are inventors on a patent application related to targeting p38γ and Thr-205 tau in Alzheimer’s and other neurodegenerative diseases (Australian Patent Number APA#2016900764).

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Ittner, A., Asih, P.R., Tan, A.R.P. et al. Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ. Acta Neuropathol 140, 279–294 (2020). https://doi.org/10.1007/s00401-020-02191-1

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