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  1. Article ; Online: Roles of Siglecs in neurodegenerative diseases.

    Siew, Jian Jing / Chern, Yijuang / Khoo, Kay-Hooi / Angata, Takashi

    Molecular aspects of medicine

    2022  Volume 90, Page(s) 101141

    Abstract: Microglia are resident myeloid cells in the central nervous system (CNS) with a unique developmental origin, playing essential roles in developing and maintaining the CNS environment. Recent studies have revealed the involvement of microglia in ... ...

    Abstract Microglia are resident myeloid cells in the central nervous system (CNS) with a unique developmental origin, playing essential roles in developing and maintaining the CNS environment. Recent studies have revealed the involvement of microglia in neurodegenerative diseases, such as Alzheimer's disease, through the modulation of neuroinflammation. Several members of the Siglec family of sialic acid recognition proteins are expressed on microglia. Since the discovery of the genetic association between a polymorphism in the CD33 gene and late-onset Alzheimer's disease, significant efforts have been made to elucidate the molecular mechanism underlying the association between the polymorphism and Alzheimer's disease. Furthermore, recent studies have revealed additional potential associations between Siglecs and Alzheimer's disease, implying that the reduced signal from inhibitory Siglec may have an overall protective effect in lowering the disease risk. Evidences suggesting the involvement of Siglecs in other neurodegenerative diseases are also emerging. These findings could help us predict the roles of Siglecs in other neurodegenerative diseases. However, little is known about the functionally relevant Siglec ligands in the brain, which represents a new frontier. Understanding how microglial Siglecs and their ligands in CNS contribute to the regulation of CNS homeostasis and pathogenesis of neurodegenerative diseases may provide us with a new avenue for disease prevention and intervention.
    MeSH term(s) Humans ; Sialic Acid Binding Immunoglobulin-like Lectins/genetics ; Sialic Acid Binding Immunoglobulin-like Lectins/metabolism ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Ligands ; Microglia/metabolism
    Chemical Substances Sialic Acid Binding Immunoglobulin-like Lectins ; Ligands
    Language English
    Publishing date 2022-09-09
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 197640-0
    ISSN 1872-9452 ; 0098-2997
    ISSN (online) 1872-9452
    ISSN 0098-2997
    DOI 10.1016/j.mam.2022.101141
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1189: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article: Microglial Lectins in Health and Neurological Diseases.

    Siew, Jian Jing / Chern, Yijuang

    Frontiers in molecular neuroscience

    2018  Volume 11, Page(s) 158

    Abstract: Microglia are the innate sentinels of the central nervous system (CNS) and are responsible for the homeostasis and immune defense of the CNS. Under the influence of the local environment and cell-cell interaction, microglia exhibit a multidimensional and ...

    Abstract Microglia are the innate sentinels of the central nervous system (CNS) and are responsible for the homeostasis and immune defense of the CNS. Under the influence of the local environment and cell-cell interaction, microglia exhibit a multidimensional and context-dependent phenotypes that can be cytotoxic and neuroprotective. Recent studies suggest that microglia express multitudinous types of lectins, including galectins, Siglecs, mannose-binding lectins (MBLs) and other glycan binding proteins. Because most studies that examine lectins focus on the peripheral system, the functions of lectins have not been critically investigated in the CNS. In addition, the types of brain cells that contribute to the altered levels of lectins present in diseases are often unclear. In this review, we will discuss how galectins, Siglecs, selectins and MBLs contribute to the dynamic functions of microglia. The interacting ligands of these lectins are complex glycoconjugates, which consist of glycoproteins and glycolipids that are expressed on microglia or surrounding cells. The current understanding of the heterogeneity and functions of glycans in the brain is limited. Galectins are a group of pleotropic proteins that recognize both β-galactoside-containing glycans and non- β-galactoside-containing proteins. The function and regulation of galectins have been implicated in immunomodulation, neuroinflammation, apoptosis, phagocytosis and oxidative bursts. Most Siglecs are expressed at a low level on the plasma membrane and bind to sialic acid residues for immunosurveillance and cell-cell communication. Siglecs are classified based on their inhibitory and activatory downstream signaling properties. Inhibitory Siglecs negatively regulate microglia activation upon recognizing the intact sialic acid patterns and vice versa. MBLs are expressed upon infection in cytoplasm and can be secreted in order to recognize molecules containing terminal mannose as an innate immune defense machinery. Most importantly, multiple studies have reported dysregulation of lectins in neurological disorders. Here, we reviewed recent studies on microglial lectins and their functions in CNS health and disease, and suggest that these lectin families are novel, potent therapeutic targets for neurological diseases.
    Language English
    Publishing date 2018-05-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2018.00158
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Galectin-3 aggravates microglial activation and tau transmission in tauopathy.

    Siew, Jian Jing / Chen, Hui-Mei / Chiu, Feng-Lan / Lee, Chia-Wei / Chang, Yao-Ming / Chen, Hung-Lin / Nguyen, Thi Ngoc Anh / Liao, Hung-Ting / Liu, Mengyu / Hagar, Hsiao-Tien / Sun, Yung-Chen / Lai, Hsing-Lin / Kuo, Min-Hao / Blum, David / Buée, Luc / Jin, Lee-Way / Chen, Shih-Yu / Ko, Tai-Ming / Huang, Jie-Rong /
    Kuo, Hung-Chih / Liu, Fu-Tong / Chern, Yijuang

    The Journal of clinical investigation

    2024  Volume 134, Issue 2

    Abstract: Alzheimer's disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. ... ...

    Abstract Alzheimer's disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.
    MeSH term(s) Animals ; Humans ; Mice ; Alzheimer Disease/pathology ; Disease Models, Animal ; Galectin 3/genetics ; Galectin 3/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Mice, Transgenic ; Microglia/pathology ; tau Proteins/genetics ; tau Proteins/metabolism ; Tauopathies/genetics ; Tauopathies/metabolism
    Chemical Substances Galectin 3 ; tau Proteins ; LGALS3 protein, human
    Language English
    Publishing date 2024-01-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI165523
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.184: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Altered behavioral responses to gamma-aminobutyric acid pharmacological agents in a mouse model of Huntington's disease.

    Hsu, Yi-Ting / Chang, Ya-Gin / Chang, Ching-Pang / Siew, Jian-Jing / Chen, Hui-Mei / Tsai, Chon-Haw / Chern, Yijuang

    Movement disorders : official journal of the Movement Disorder Society

    2017  Volume 32, Issue 11, Page(s) 1600–1609

    Abstract: Background: Disruptions in gamma-aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the ... ...

    Abstract Background: Disruptions in gamma-aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease.
    Methods: We treated wild-type and R6/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABA
    Results: The R6/2 mice were less sensitive to the sedative effects of both drugs, suggesting reduced function of GABA
    Conclusions: The dysregulated GABAergic responses and altered expression levels of GABA
    MeSH term(s) Animals ; Behavior, Animal/drug effects ; Cerebral Cortex/drug effects ; Cerebral Cortex/metabolism ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Diazepam/pharmacology ; Disease Models, Animal ; Female ; GABA Agonists/pharmacology ; GABA Modulators/pharmacology ; Huntington Disease/metabolism ; Isoxazoles/pharmacology ; Male ; Mice ; Mice, Transgenic ; Receptors, GABA-A/drug effects ; Receptors, GABA-A/metabolism
    Chemical Substances GABA Agonists ; GABA Modulators ; Isoxazoles ; Receptors, GABA-A ; gaboxadol (K1M5RVL18S) ; Diazepam (Q3JTX2Q7TU)
    Language English
    Publishing date 2017-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 607633-6
    ISSN 1531-8257 ; 0885-3185
    ISSN (online) 1531-8257
    ISSN 0885-3185
    DOI 10.1002/mds.27107
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2555: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 238: Show issues

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  5. Article ; Online: Functional roles of ST8SIA3-mediated sialylation of striatal dopamine D

    Lin, Chien-Yu / Lai, Hsing-Lin / Chen, Hui-Mei / Siew, Jian-Jing / Hsiao, Cheng-Te / Chang, Hua-Chien / Liao, Kuo-Shiang / Tsai, Shih-Chieh / Wu, Chung-Yi / Kitajima, Ken / Sato, Chihiro / Khoo, Kay-Hooi / Chern, Yijuang

    Translational psychiatry

    2019  Volume 9, Issue 1, Page(s) 209

    Abstract: Sialic acids are typically added to the end of glycoconjugates by sialyltransferases. Among the six ST8 α-N-acetyl-neuraminide α-2,8-sialyltransferases (ST8SIA) existing in adult brains, ST8SIA2 is a schizophrenia-associated gene. However, the in vivo ... ...

    Abstract Sialic acids are typically added to the end of glycoconjugates by sialyltransferases. Among the six ST8 α-N-acetyl-neuraminide α-2,8-sialyltransferases (ST8SIA) existing in adult brains, ST8SIA2 is a schizophrenia-associated gene. However, the in vivo substrates and physiological functions of most sialyltransferases are currently unknown. The ST8SIA3 is enriched in the striatum. Here, we showed that ablation of St8sia3 in mice (St8sia3-KO) led to fewer disialylated and trisialylated terminal glycotopes in the striatum of St8sia3-KO mice. Moreover, the apparent sizes of several striatum-enriched G-protein-coupled receptors (GPCRs) (including the adenosine A
    MeSH term(s) Animals ; Corpus Striatum/metabolism ; Membrane Microdomains/metabolism ; Mice ; Mice, Knockout ; Neurons/metabolism ; Receptor, Adenosine A2A/metabolism ; Receptors, Dopamine D2/metabolism ; Sialyltransferases/genetics ; Sialyltransferases/metabolism
    Chemical Substances Receptor, Adenosine A2A ; Receptors, Dopamine D2 ; Sia(alpha2,3)Gal(beta1,4)GlcNAc alpha-2,8-sialyltransferase (EC 2.4.99.-) ; Sialyltransferases (EC 2.4.99.-)
    Language English
    Publishing date 2019-08-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2609311-X
    ISSN 2158-3188 ; 2158-3188
    ISSN (online) 2158-3188
    ISSN 2158-3188
    DOI 10.1038/s41398-019-0529-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington's disease.

    Siew, Jian Jing / Chen, Hui-Mei / Chen, Huan-Yuan / Chen, Hung-Lin / Chen, Chiung-Mei / Soong, Bing-Wen / Wu, Yih-Ru / Chang, Ching-Pang / Chan, Yi-Chen / Lin, Chun-Hung / Liu, Fu-Tong / Chern, Yijuang

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 3473

    Abstract: Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in ... ...

    Abstract Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
    MeSH term(s) Adult ; Animals ; Brain/cytology ; Brain/pathology ; Brain/ultrastructure ; Disease Models, Animal ; Disease Progression ; Female ; Galectin 3/blood ; Galectin 3/genetics ; Galectin 3/metabolism ; Gene Knockdown Techniques ; Humans ; Huntington Disease/blood ; Huntington Disease/diagnosis ; Huntington Disease/pathology ; Inflammasomes/metabolism ; Lysosomes/metabolism ; Lysosomes/ultrastructure ; Male ; Mice ; Microglia/cytology ; Microglia/pathology ; Microglia/ultrastructure ; Microscopy, Electron, Transmission ; Middle Aged ; Severity of Illness Index ; Up-Regulation
    Chemical Substances Galectin 3 ; Inflammasomes ; LGALS3 protein, human ; Lgals3 protein, mouse
    Language English
    Publishing date 2019-08-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-11441-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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