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Genetic ablation of the p66Shc adaptor protein reverses cognitive deficits and improves mitochondrial function in an APP transgenic mouse model of Alzheimer’s disease

Molecular Psychiatry volume 22, pages 605–614 (2017)Cite this article

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Abstract

The mammalian ShcA adaptor protein p66Shc is a key regulator of mitochondrial reactive oxygen species (ROS) production and has previously been shown to mediate amyloid β (Aβ)-peptide-induced cytotoxicity in vitro. Moreover, p66Shc is involved in mammalian longevity and lifespan determination as revealed in the p66Shc knockout mice, which are characterized by a 30% prolonged lifespan, lower ROS levels and protection from age-related impairment of physical and cognitive performance. In this study, we hypothesized a role for p66Shc in Aβ-induced toxicity in vivo and investigated the effects of genetic p66Shc deletion in the PSAPP transgenic mice, an established Alzheimer’s disease mouse model of β-amyloidosis. p66Shc-ablated PSAPP mice were characterized by an improved survival and a complete rescue of Aβ-induced cognitive deficits at the age of 15 months. Importantly, these beneficial effects on survival and cognitive performance were independent of Aβ levels and amyloid plaque deposition, but were associated with improved brain mitochondrial respiration, a reversal of mitochondrial complex I dysfunction, restored adenosine triphosphate production and reduced ROS levels. The results of this study support a role for p66Shc in Aβ-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66Shc ablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment.

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Acknowledgements

This study was supported in part by the Hartmann Müller Foundation (LK), by the Hermann Klaus Foundation (LK) and by the Forschungskredit Grant K-82031-03-01 of the University of Zurich (RD).

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Authors and Affiliations

  1. Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland

    R Derungs, T Welt, C Tackenberg, C Späni, F Wirth, R M Nitsch & L Kulic

  2. Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland

    R Derungs, G G Camici, C Tackenberg, C Späni, F Wirth, R M Nitsch & L Kulic

  3. Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

    G G Camici & R D Spescha

  4. Neurobiology Research Laboratory, Psychiatric University Clinic, Basel, Switzerland

    A Grimm & A Eckert

  5. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

    L Kulic

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  1. R Derungs
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Derungs, R., Camici, G., Spescha, R. et al. Genetic ablation of the p66Shc adaptor protein reverses cognitive deficits and improves mitochondrial function in an APP transgenic mouse model of Alzheimer’s disease. Mol Psychiatry 22, 605–614 (2017). https://doi.org/10.1038/mp.2016.112

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