Difference between revisions of "Derungs 2017 Mol Psychiatry"
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|abstract=The mammalian ShcA adaptor protein p66<sup>Shc</sup> 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, p66<sup>Shc</sup> is involved in mammalian longevity and lifespan determination as revealed in the p66<sup>Shc</sup> 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 p66<sup>Shc</sup> in Aβ-induced toxicity ''in vivo'' and investigated the effects of genetic p66<sup>Shc</sup> deletion in the PSAPP transgenic mice, an established Alzheimer's disease mouse model of β-amyloidosis. p66<sup>Shc</sup>-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 p66<sup>Shc</sup> in Aβ-related mitochondrial dysfunction and oxidative damage ''in vivo'', and suggest that p66<sup>Shc</sup> ablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment. | |abstract=The mammalian ShcA adaptor protein p66<sup>Shc</sup> 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, p66<sup>Shc</sup> is involved in mammalian longevity and lifespan determination as revealed in the p66<sup>Shc</sup> 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 p66<sup>Shc</sup> in Aβ-induced toxicity ''in vivo'' and investigated the effects of genetic p66<sup>Shc</sup> deletion in the PSAPP transgenic mice, an established Alzheimer's disease mouse model of β-amyloidosis. p66<sup>Shc</sup>-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 p66<sup>Shc</sup> in Aβ-related mitochondrial dysfunction and oxidative damage ''in vivo'', and suggest that p66<sup>Shc</sup> ablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment. | ||
|editor=[[Kandolf G]], | |editor=[[Kandolf G]], | ||
|mipnetlab=CH Basel Eckert A | |||
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|tissues=Nervous system | |tissues=Nervous system | ||
|preparations=Isolated mitochondria | |preparations=Isolated mitochondria | ||
|couplingstates=LEAK, OXPHOS, | |enzymes=Complex I, Complex IV;cytochrome c oxidase | ||
|couplingstates=LEAK, OXPHOS, ET | |||
|pathways=N | |pathways=N | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional= | |additional=2017-05, | ||
}} | }} | ||
Latest revision as of 10:59, 25 June 2019
| Derungs R, Camici GG, Spescha RD, Welt T, Tackenberg C, Späni C, Wirth F, Grimm A, Eckert A, Nitsch RM, Kulic L (2017) 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 22:605-14. |
Derungs R, Camici GG, Spescha RD, Welt T, Tackenberg C, Spaini C, Wirth F, Grimm A, Eckert A, Nitsch RM, Kulic L (2017) Mol Psychiatry
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.
• Bioblast editor: Kandolf G • O2k-Network Lab: CH Basel Eckert A
Labels: MiParea: Respiration, Genetic knockout;overexpression
Pathology: Aging;senescence, Alzheimer's
Organism: Mouse Tissue;cell: Nervous system Preparation: Isolated mitochondria Enzyme: Complex I, Complex IV;cytochrome c oxidase
Coupling state: LEAK, OXPHOS, ET Pathway: N HRR: Oxygraph-2k
2017-05
