Intranasal NAP (davunetide) decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing α-synuclein

Authors

  • Iddo Magen,

    1. Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, California
    2. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
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    • Iddo Magen and Regina Ostritsky contributed equally to this work.
  • Regina Ostritsky,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
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    • Iddo Magen and Regina Ostritsky contributed equally to this work.
  • Franziska Richter,

    1. Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, California
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  • Chunni Zhu,

    1. Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, California
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  • Sheila M. Fleming,

    1. Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, California
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  • Vincent Lemesre,

    1. Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, California
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  • Alistair J. Stewart,

    1. Allon Therapeutics Inc., Vancouver, British Columbia, Canada
    2. Paladin Labs Inc., St Laurent, Quebec, Canada
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  • Bruce H. Morimoto,

    1. Allon Therapeutics Inc., Vancouver, British Columbia, Canada
    2. Celerion, Lincoln, Nebraska
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  • Illana Gozes,

    Corresponding author
    1. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
    • Correspondence

      Marie-Françoise Chesselet, Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769. Tel: 310-267-1781; Fax: 310-267-1786; E-mail: mchesselet@mednet.ucla.edu

      Illana Gozes, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Director, Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv 69978, Israel. Tel: 972-3-6407240; Fax: 972-3-640-8541; E-mail: igozes@post.tau.ac.il

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  • Marie-Françoise Chesselet

    Corresponding author
    1. Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, California
    • Correspondence

      Marie-Françoise Chesselet, Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769. Tel: 310-267-1781; Fax: 310-267-1786; E-mail: mchesselet@mednet.ucla.edu

      Illana Gozes, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Director, Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv 69978, Israel. Tel: 972-3-6407240; Fax: 972-3-640-8541; E-mail: igozes@post.tau.ac.il

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Abstract

Genome-wide association studies have identified strong associations between the risk of developing Parkinson's disease (PD) and polymorphisms in the genes encoding α-synuclein and the microtubule-associated protein tau. However, the contribution of tau and its phosphorylated form (p-tau) to α-synuclein-induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (davunetide), an eight-amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild-type human α-synuclein (Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the p-tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p-tau/tau levels in the subcortical region while a higher dose of 15 μg/mouse per day induced a decrease in p-tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1-aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits.

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