TY - JOUR
T1 - Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer’s disease
AU - Wei, Yu
AU - Shin, Mi Ryung
AU - Sesti, Federico
N1 - Funding Information:
The frozen samples of human tissue were requested through the Neurobiobank repository of the National Institutes of Health and were kindly provided by the Harvard Brain Tissue Resource Center which is supported in part by HHSN-271-2013-00030C. The 3xTg-AD mouse was a gift of Dr. Cheryl Dreyfus. We thank Dr. Surindo Singh for help with crossing the transgenic mice and Dr. Barbara Viviani for critical reading of the manuscript. This work was supported by a NSF grant (1456675) and a NIH grant (NS096619) to F.S.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Oxidative modification of the voltage-gated K + channel subfamily B member 1 (KCNB1, Kv2.1) is emerging as a mechanism of neuronal vulnerability potentially capable of affecting multiple conditions associated with oxidative stress, from normal aging to neurodegenerative disease. In this study we report that oxidation of KCNB1 channels is exacerbated in the post mortem brains of Alzheimer’s disease (AD) donors compared to age-matched controls. In addition, phosphorylation of Focal Adhesion kinases (FAK) and Src tyrosine kinases, two key signaling steps that follow KCNB1 oxidation, is also strengthened in AD vs. control brains. Quadruple transgenic mice expressing a non-oxidizable form of KCNB1 in the 3xTg-AD background (APP SWE , PS1 M146V , and tau P301L ), exhibit improved working memory along with reduced brain inflammation, protein carbonylation and intraneuronal β-amyloid (Aβ) compared to 3xTg-AD mice or mice expressing the wild type (WT) KCNB1 channel. We conclude that oxidation of KCNB1 channels is a mechanism of neuronal vulnerability that is pervasive in the vertebrate brain.
AB - Oxidative modification of the voltage-gated K + channel subfamily B member 1 (KCNB1, Kv2.1) is emerging as a mechanism of neuronal vulnerability potentially capable of affecting multiple conditions associated with oxidative stress, from normal aging to neurodegenerative disease. In this study we report that oxidation of KCNB1 channels is exacerbated in the post mortem brains of Alzheimer’s disease (AD) donors compared to age-matched controls. In addition, phosphorylation of Focal Adhesion kinases (FAK) and Src tyrosine kinases, two key signaling steps that follow KCNB1 oxidation, is also strengthened in AD vs. control brains. Quadruple transgenic mice expressing a non-oxidizable form of KCNB1 in the 3xTg-AD background (APP SWE , PS1 M146V , and tau P301L ), exhibit improved working memory along with reduced brain inflammation, protein carbonylation and intraneuronal β-amyloid (Aβ) compared to 3xTg-AD mice or mice expressing the wild type (WT) KCNB1 channel. We conclude that oxidation of KCNB1 channels is a mechanism of neuronal vulnerability that is pervasive in the vertebrate brain.
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U2 - 10.1038/s41419-018-0886-1
DO - 10.1038/s41419-018-0886-1
M3 - Article
C2 - 30050035
AN - SCOPUS:85050773949
SN - 2041-4889
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 8
M1 - 820
ER -