P66Shc Signaling Mediates Diabetes-Related Cognitive Decline

Yohei Minami; Noriyuki Sonoda; Eiichi Hayashida; Hiroaki Makimura; Makoto Ide; Noriko Ikeda; Masahiro Ohgidani; Takahiro A. Kato; Yoshihiro Seki; Yasutaka Maeda; Shigenobu Kanba; Ryoichi Takayanagi; Yoshihiro Ogawa; Toyoshi Inoguchi

doi:10.1038/s41598-018-21426-6

P66Shc Signaling Mediates Diabetes-Related Cognitive Decline

Yohei Minami, Noriyuki Sonoda, Eiichi Hayashida, Hiroaki Makimura, Makoto Ide, Noriko Ikeda, Masahiro Ohgidani, Takahiro A. Kato, Yoshihiro Seki, Yasutaka Maeda, Shigenobu Kanba, Ryoichi Takayanagi, Yoshihiro Ogawa, Toyoshi Inoguchi

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19 Citations (Scopus)

Abstract

Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.

Original language	English
Article number	3213
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-21426-6
Publication status	Published - Dec 1 2018

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10.1038/s41598-018-21426-6

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title = "P66Shc Signaling Mediates Diabetes-Related Cognitive Decline",

abstract = "Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.",

author = "Yohei Minami and Noriyuki Sonoda and Eiichi Hayashida and Hiroaki Makimura and Makoto Ide and Noriko Ikeda and Masahiro Ohgidani and Kato, {Takahiro A.} and Yoshihiro Seki and Yasutaka Maeda and Shigenobu Kanba and Ryoichi Takayanagi and Yoshihiro Ogawa and Toyoshi Inoguchi",

note = "Funding Information: We thank the Research Support Center, Graduate School of Medical Sciences, Kyushu University for their technical support. We also thank Ms. Mikiko Nakano for technical assistance. This study was supported by Grants-in-Aid for Rare and Intractable Diseases (to KH and KK) from the Ministry of Health, Labor, and Welfare of the Japanese Government, KAKENHI, the Japan Society for the Promotion of Science (“Kiban C” 17889556 to NS) and in part by the Special Coordination Funds for Promoting Science and Technology (SCF; funding program of the Innovation Center for Medical Redox Navigation), Japan. The authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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doi = "10.1038/s41598-018-21426-6",

language = "English",

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T1 - P66Shc Signaling Mediates Diabetes-Related Cognitive Decline

AU - Minami, Yohei

AU - Sonoda, Noriyuki

AU - Hayashida, Eiichi

AU - Makimura, Hiroaki

AU - Ide, Makoto

AU - Ikeda, Noriko

AU - Ohgidani, Masahiro

AU - Kato, Takahiro A.

AU - Seki, Yoshihiro

AU - Maeda, Yasutaka

AU - Kanba, Shigenobu

AU - Takayanagi, Ryoichi

AU - Ogawa, Yoshihiro

AU - Inoguchi, Toyoshi

N1 - Funding Information: We thank the Research Support Center, Graduate School of Medical Sciences, Kyushu University for their technical support. We also thank Ms. Mikiko Nakano for technical assistance. This study was supported by Grants-in-Aid for Rare and Intractable Diseases (to KH and KK) from the Ministry of Health, Labor, and Welfare of the Japanese Government, KAKENHI, the Japan Society for the Promotion of Science (“Kiban C” 17889556 to NS) and in part by the Special Coordination Funds for Promoting Science and Technology (SCF; funding program of the Innovation Center for Medical Redox Navigation), Japan. The authors declare no conflicts of interest. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.

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P66Shc Signaling Mediates Diabetes-Related Cognitive Decline

Abstract

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