Derungs 2017 Mol Psychiatry
| Derungs R, Camici GG, Spescha RD, Welt T, Tackenberg C, SpΓ€ni 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 Ξ² (AΞ²)-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 AΞ²-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 Ξ²-amyloidosis. p66Shc-ablated PSAPP mice were characterized by an improved survival and a complete rescue of AΞ²-induced cognitive deficits at the age of 15 months. Importantly, these beneficial effects on survival and cognitive performance were independent of AΞ² 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 AΞ²-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66Shc ablation may be a promising novel therapeutic strategy against AΞ²-induced toxicity and cognitive impairment.
β’ Bioblast editor: Kandolf G β’ 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
Coupling state: LEAK, OXPHOS, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property.
Pathway: N
HRR: Oxygraph-2k
Labels, 2017-05
