title: Aberrant expression of the pore-forming KATPchannel subunit Kir6.2 in hippocampal reactive astrocytes in the 3xTg-AD mouse model and human Alzheimer's disease.
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 KATPchannels, 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: 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.
authors: Chelsea M
authors: CM
authors: Griffith
authors: Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan 410013, China.
authors: Mi-Xin
authors: MX
authors: Xie
authors: 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.
authors: Wen-Ying
authors: WY
authors: Qiu
authors: 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.
authors: Andrew A
authors: AA
authors: Sharp
authors: 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.
authors: Chao
authors: C
authors: Ma
authors: Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan 410013, China.
authors: Aihua
authors: A
authors: Pan
authors: 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.
authors: Xiao-Xin
authors: XX
authors: Yan
authors: 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.
authors: Peter R
authors: PR
authors: Patrylo
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D005904:Glial Fibrillary Acidic Protein; D024661:Potassium Channels, Inwardly Rectifying; D016875:tau Proteins; D000099161:Kcnj11 Channel
keywords: CA1; GFAP; Kir6.1; astrogliosis; glutamine synthetase; inwardly rectifying potassium channels