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Genetic ablation of the p66(Shc) adaptor protein reverses cognitive deficits and improves mitochondrial function in an APP transgenic mouse model of Alzheimer's disease


Derungs, R; Camici, G G; Spescha, R D; Welt, T; Tackenberg, C; Späni, C; Wirth, F; Grimm, A; Eckert, A; Nitsch, R M; Kulic, L (2017). Genetic ablation of the p66(Shc) adaptor protein reverses cognitive deficits and improves mitochondrial function in an APP transgenic mouse model of Alzheimer's disease. Molecular Psychiatry, 22(4):605-614.

Abstract

The mammalian ShcA adaptor protein p66(Shc) 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(Shc) is involved in mammalian longevity and lifespan determination as revealed in the p66(Shc) 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(Shc) in Aβ-induced toxicity in vivo and investigated the effects of genetic p66(Shc) deletion in the PSAPP transgenic mice, an established Alzheimer's disease mouse model of β-amyloidosis. p66(Shc)-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(Shc) in Aβ-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66(Shc) ablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment.Molecular Psychiatry advance online publication, 19 July 2016; doi:10.1038/mp.2016.112.

Abstract

The mammalian ShcA adaptor protein p66(Shc) 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(Shc) is involved in mammalian longevity and lifespan determination as revealed in the p66(Shc) 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(Shc) in Aβ-induced toxicity in vivo and investigated the effects of genetic p66(Shc) deletion in the PSAPP transgenic mice, an established Alzheimer's disease mouse model of β-amyloidosis. p66(Shc)-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(Shc) in Aβ-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66(Shc) ablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment.Molecular Psychiatry advance online publication, 19 July 2016; doi:10.1038/mp.2016.112.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2017
Deposited On:04 Jan 2017 16:22
Last Modified:21 Nov 2017 18:50
Publisher:Nature Publishing Group
ISSN:1359-4184
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/mp.2016.112
PubMed ID:27431297

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