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Aberrant expression of the pore-forming KATP channel subunit Kir6.2 in hippocampal reactive astrocytes in the 3xTg-AD mouse model and human Alzheimer's disease.
Neuroscience. 2016 Nov 12; 336:81-101.N

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Aβ) deposition, neurofibrillary tangles and cognitive decline. Recent pharmacologic studies have found that ATP-sensitive potassium (KATP) channels may play a role in AD and could be a potential therapeutic target. Interestingly, these channels are found in both neurons and astrocytes. One of the hallmarks associated with AD is reactive gliosis and a change in astrocytic function has been identified in several neuropathological conditions including AD. Thus the goal of this study was to examine whether the pore-forming subunits of KATP channels, Kir6.1 and Kir6.2, are altered in the hippocampus in a cell type-specific manner of the 3xTg-AD mouse model of AD and in human AD tissue obtained from the Chinese brain bank. Specifically, in old 3xTg-AD mice, and age-matched controls, we examined glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), Kir6.1 and Kir6.2 in hippocampal region CA1 with a combination of immunoblotting and immunohistochemistry (IHC). A time point was selected when memory impairment and histopathological changes have been reported to occur in 3xTg-AD mice. In human AD and age-matched control tissue IHC experiments were performed using GFAP and Kir6.2. In the hippocampus of 3xTg-AD mice, compared to wild-type controls, Western blots showed a significant increase in GFAP indicating astrogliosis. Further, there was an increase in Kir6.2, but not Kir6.1 in the plasma membrane fraction. IHC examination of hippocampal region CA1 in 3xTg-AD sections revealed an increase in Kir6.2 immunoreactivity (IR) in astrocytes as identified by GFAP and GS. In human AD tissue similar data were obtained. There was an increase in GFAP-IR in the stratum oriens (SO) and alveus (ALV) of CA1 concomitant with an increase in Kir6.2-IR in cells with an astrocytic-like morphology. Dual immunofluorescence revealed a dramatic increase in co-localization of Kir6.2-IR and GFAP-IR. Taken together, these data demonstrate that increased Kir6.2 is seen in reactive astrocytes in old 3xTg-AD mice and human AD tissue. These changes could dramatically alter astrocytic function and subsequently contribute to AD phenotype in either a compensatory or pathophysiological manner.

Authors+Show Affiliations

Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University Carbondale, IL 62901, USA.Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan 410013, China.Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, Department of Human Anatomy, Histology & Embryology, School of Basic Medicine, Peking Union Medical College, Beijing 100730, China.Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University Carbondale, IL 62901, USA.Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, Department of Human Anatomy, Histology & Embryology, School of Basic Medicine, Peking Union Medical College, Beijing 100730, China.Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan 410013, China.Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan 410013, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Changsha, Hunan 410008, China.Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University Carbondale, IL 62901, USA. Electronic address: ppatrylo@siumed.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27586053

Citation

Griffith, Chelsea M., et al. "Aberrant Expression of the Pore-forming KATP Channel Subunit Kir6.2 in Hippocampal Reactive Astrocytes in the 3xTg-AD Mouse Model and Human Alzheimer's Disease." Neuroscience, vol. 336, 2016, pp. 81-101.
Griffith CM, Xie MX, Qiu WY, et al. Aberrant expression of the pore-forming KATP channel subunit Kir6.2 in hippocampal reactive astrocytes in the 3xTg-AD mouse model and human Alzheimer's disease. Neuroscience. 2016;336:81-101.
Griffith, C. M., Xie, M. X., Qiu, W. Y., Sharp, A. A., Ma, C., Pan, A., Yan, X. X., & Patrylo, P. R. (2016). Aberrant expression of the pore-forming KATP channel subunit Kir6.2 in hippocampal reactive astrocytes in the 3xTg-AD mouse model and human Alzheimer's disease. Neuroscience, 336, 81-101. https://doi.org/10.1016/j.neuroscience.2016.08.034
Griffith CM, et al. Aberrant Expression of the Pore-forming KATP Channel Subunit Kir6.2 in Hippocampal Reactive Astrocytes in the 3xTg-AD Mouse Model and Human Alzheimer's Disease. Neuroscience. 2016 Nov 12;336:81-101. PubMed PMID: 27586053.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aberrant expression of the pore-forming KATP channel subunit Kir6.2 in hippocampal reactive astrocytes in the 3xTg-AD mouse model and human Alzheimer's disease. AU - Griffith,Chelsea M, AU - Xie,Mi-Xin, AU - Qiu,Wen-Ying, AU - Sharp,Andrew A, AU - Ma,Chao, AU - Pan,Aihua, AU - Yan,Xiao-Xin, AU - Patrylo,Peter R, Y1 - 2016/08/29/ PY - 2016/02/22/received PY - 2016/08/15/revised PY - 2016/08/20/accepted PY - 2016/9/3/pubmed PY - 2017/10/13/medline PY - 2016/9/3/entrez KW - CA1 KW - GFAP KW - Kir6.1 KW - astrogliosis KW - glutamine synthetase KW - inwardly rectifying potassium channels SP - 81 EP - 101 JF - Neuroscience JO - Neuroscience VL - 336 N2 - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Aβ) deposition, neurofibrillary tangles and cognitive decline. Recent pharmacologic studies have found that ATP-sensitive potassium (KATP) channels may play a role in AD and could be a potential therapeutic target. Interestingly, these channels are found in both neurons and astrocytes. One of the hallmarks associated with AD is reactive gliosis and a change in astrocytic function has been identified in several neuropathological conditions including AD. Thus the goal of this study was to examine whether the pore-forming subunits of KATP channels, Kir6.1 and Kir6.2, are altered in the hippocampus in a cell type-specific manner of the 3xTg-AD mouse model of AD and in human AD tissue obtained from the Chinese brain bank. Specifically, in old 3xTg-AD mice, and age-matched controls, we examined glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), Kir6.1 and Kir6.2 in hippocampal region CA1 with a combination of immunoblotting and immunohistochemistry (IHC). A time point was selected when memory impairment and histopathological changes have been reported to occur in 3xTg-AD mice. In human AD and age-matched control tissue IHC experiments were performed using GFAP and Kir6.2. In the hippocampus of 3xTg-AD mice, compared to wild-type controls, Western blots showed a significant increase in GFAP indicating astrogliosis. Further, there was an increase in Kir6.2, but not Kir6.1 in the plasma membrane fraction. IHC examination of hippocampal region CA1 in 3xTg-AD sections revealed an increase in Kir6.2 immunoreactivity (IR) in astrocytes as identified by GFAP and GS. In human AD tissue similar data were obtained. There was an increase in GFAP-IR in the stratum oriens (SO) and alveus (ALV) of CA1 concomitant with an increase in Kir6.2-IR in cells with an astrocytic-like morphology. Dual immunofluorescence revealed a dramatic increase in co-localization of Kir6.2-IR and GFAP-IR. Taken together, these data demonstrate that increased Kir6.2 is seen in reactive astrocytes in old 3xTg-AD mice and human AD tissue. These changes could dramatically alter astrocytic function and subsequently contribute to AD phenotype in either a compensatory or pathophysiological manner. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/27586053/Aberrant_expression_of_the_pore_forming_KATP_channel_subunit_Kir6_2_in_hippocampal_reactive_astrocytes_in_the_3xTg_AD_mouse_model_and_human_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(16)30407-9 DB - PRIME DP - Unbound Medicine ER -