title: Genetic ablation of the p66Shcadaptor protein reverses cognitive deficits and improves mitochondrial function in an APP transgenic mouse model of Alzheimer's disease.
abstract: The mammalian ShcA adaptor protein p66Shcis 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, p66Shcis involved in mammalian longevity and lifespan determination as revealed in the p66Shcknockout 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 p66Shcin Aβ-induced toxicity in vivo and investigated the effects of genetic p66Shcdeletion 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 p66Shcin Aβ-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66Shcablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment.
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland.|Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Derungs
authors.affiliation: Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.|Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
authors.forename: G G
authors.initials: GG
authors.lastname: Camici
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
authors.forename: R D
authors.initials: RD
authors.lastname: Spescha
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Welt
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland.|Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Tackenberg
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland.|Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Späni
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland.|Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Wirth
authors.affiliation: Neurobiology Research Laboratory, Psychiatric University Clinic, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Grimm
authors.affiliation: Neurobiology Research Laboratory, Psychiatric University Clinic, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Eckert
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland.|Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
authors.forename: R M
authors.initials: RM
authors.lastname: Nitsch
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren, Switzerland.|Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Kulic
mesh_terms: D055011:Ablation Techniques / Q000379:methods; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1