title: Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders.
abstract: Human immunodeficiency virus (HIV) encephalitis and degeneration of cerebral cortex are established histopathologies of HIV-associated neurocognitive disorders (HAND). We previously reported decreased excitatory amino acid transporter-2 (EAAT-2) and astrocytic apoptosis in cortical degeneration using SIVmac239 and simian-human immunodeficiency virus (SHIV)-infected macaques and human AIDS autopsy cases. In the present study, we added highly pathogenic SIVsm543-3-infected macaques. These animals showed similar degenerative changes in the frontal cortex. Using 11 SIV-infected macaques, three SIVsm543-3, five SIVmac239 and three SHIV, we compared brain pathology caused by three different viruses and further analyzed the pathogenic process of HAND. We noticed vacuolar changes in perivascular processes of astrocytes by electron microscopy, and examined expression of astrocyte-specific protein aquaporin-4 (AQP4) by immunohistochemistry. APQ4 was diffusely positive in the neuropil and perivascular area in control brains. There was patchy or diffuse decrease of AQP4 staining in the neuropil of SIV-infected macaques, which was associated with EAAT-2 staining by double immunostaining. A quantitative analysis demonstrated significant positive correlation between areas of AQP4 and EAAT-2. Some astrocytes express EAAT-2 but not AQP4, and decrease of EAAT-2 expression tended to be less than the decrease of AQP4. Active-caspase-3 immunostaining demonstrated apoptosis of neurons and astrocytes in the area of AQP4/EAAT-2 reduction. These results suggest that AQP4 is damaged first and decrease of EAAT-2 may follow in pathogenesis of cortical degeneration. This is the first demonstration of decrease of AQP4 and its association with EAAT-2 decrease in AIDS brain, suggesting a role in the pathogenesis of HAND.
authors: Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.|Department of Basic Medical Sciences, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, China.
authors: Hui Qin
authors: HQ
authors: Xing
authors: Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.|Department of Basic Medical Sciences, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, China.
authors: Yu
authors: Y
authors: Zhang
authors: Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors: Kimiko
authors: K
authors: Izumo
authors: Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors: Shiho
authors: S
authors: Arishima
authors: Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors: Ryuji
authors: R
authors: Kubota
authors: Department of Basic Medical Sciences, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, China.
authors: Xiang
authors: X
authors: Ye
authors: Department of Basic Medical Sciences, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, China.
authors: Qiping
authors: Q
authors: Xu
authors: AIDS Research Center, National Institute of Infectious Disease, Tokyo, Japan.
authors: Kazuyasu
authors: K
authors: Mori
authors: Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors: Shuji
authors: S
authors: Izumo
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051401:Aquaporin 4 / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019581:Neuropil / Q000378:metabolism / Q000473:pathology; D015302:Simian Immunodeficiency Virus
chemical_list: D051401:Aquaporin 4; D027342:Excitatory Amino Acid Transporter 2; D053148:Caspase 3
keywords: HAND; SIVsm543-3; apoptosis of neuron and astrocytes; aquaporin-4; excitatory amino acid transporter 2