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.
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.
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
2A
receptor (A
2A
R) and dopamine D
1
/D
2
receptors (D
1
R and D
2
R)) were smaller in
St8sia3
-KO mice than in WT mice. A sialidase treatment removed the differences in the sizes of these molecules between
St8sia3
-KO and WT mice, confirming the involvement of sialylation. Expression of ST8SIA3 in the striatum of
St8sia3
-KO mice using adeno-associated viruses normalized the sizes of these proteins, demonstrating a direct role of ST8SIA3. The lack of ST8SIA3-mediated sialylation altered the distribution of these proteins in lipid rafts and the interaction between D
2
R and A
2A
R. Locomotor activity assays revealed altered pharmacological responses of
St8sia3
-KO mice to drugs targeting these receptors and verified that a greater population of D
2
R formed heteromers with A
2A
R in the striatum of
St8sia3
-KO mice. Since the A
2A
R-D
2
R heteromer is an important drug target for several basal ganglia diseases (such as schizophrenia and Parkinson’s disease), the present study not only reveals a crucial role for ST8SIA3 in striatal functions but also provides a new drug target for basal ganglia-related diseases.
Roles of Siglecs in neurodegenerative diseases Siew, Jian Jing; Chern, Yijuang; Khoo, Kay-Hooi ...
Molecular aspects of medicine,
April 2023, 2023-04-00, 20230401, Letnik:
90
Journal Article
Recenzirano
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.
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.
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
receptor (A
R) and dopamine D
/D
receptors (D
R and D
R)) were smaller in St8sia3-KO mice than in WT mice. A sialidase treatment removed the differences in the sizes of these molecules between St8sia3-KO and WT mice, confirming the involvement of sialylation. Expression of ST8SIA3 in the striatum of St8sia3-KO mice using adeno-associated viruses normalized the sizes of these proteins, demonstrating a direct role of ST8SIA3. The lack of ST8SIA3-mediated sialylation altered the distribution of these proteins in lipid rafts and the interaction between D
R and A
R. Locomotor activity assays revealed altered pharmacological responses of St8sia3-KO mice to drugs targeting these receptors and verified that a greater population of D
R formed heteromers with A
R in the striatum of St8sia3-KO mice. Since the A
R-D
R heteromer is an important drug target for several basal ganglia diseases (such as schizophrenia and Parkinson's disease), the present study not only reveals a crucial role for ST8SIA3 in striatal functions but also provides a new drug target for basal ganglia-related diseases.
博士
國立陽明大學
分子醫學博士學位學程
107
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that manifests with movement dysfunction and cognitive decline. The disease-causing mutation is ...an expansion of CAG repeats in the Huntingtin gene. The resultant mutant Huntingtin (mHTT) is present in brain cells, such as neurons and glial cells and disrupts their functions. Microglia are the innate sentinels of the brain, which play a major role in inflammatory responses. Under the influence of cell-cell interaction and environmental alteration, microglia exhibit multidimensional phenotypes that can be neurotoxic or neuroprotective. Emerging evidences showing microglia express various types of lectins that regulate glial functions. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. In Chapter 3.1, I characterized the profile of Gal3 in HD patients and two mouse models of HD. Here in, I showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity, which served as a potential biomarker for HD. Moreover, the brain levels of Gal3 were abnormally up-regulated in the microglia of patients and mice with HD than those in controls. The dysregulation of Gal3 expression in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. In Chapter 3.2, I investigated the mechanistic roles of Gal3 in the microglia of Huntington’s disease. Previous studies have demonstrated activation of NFκB by mHTT. My results demonstrated that the activation of NFκB in HD microglia causes the up-regulation of Gal3, while the abnormally up-regulated Gal3 further activated NFκB in a feed-forward loop. Such a cell-autonomous up-regulated Gal3 also accumulated at damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Intriguingly, suppression of Gal3 by genetic or pharmacology approaches improved the clearance of damaged lysosomes and ameliorated inflammation in HD microglia. In Chapter 3.3, I investigated the potential of Gal3 as a therapeutic target of HD. Knockdown of Gal3 in vivo suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor function impairment, and increased survival in HD mice. Collectively, our studies reveal a novel mechanistic roles of Gal3 in HD microglia-mediated pathogenesis and suggest that Gal3 is a novel therapeutic target.
Temperature‐dependent transport measurements are performed on the same set of chemical vapor deposition (CVD)‐grown WS2 single‐ and bilayer devices before and after atomic layer deposition (ALD) of ...HfO2. This isolates the influence of HfO2 deposition on low‐temperature carrier transport and shows that carrier mobility is not charge impurity limited as commonly thought, but due to another important but commonly overlooked factor: interface roughness. This finding is corroborated by circular dichroic photoluminescence spectroscopy, X‐ray photoemission spectroscopy, cross‐sectional scanning transmission electron microscopy, carrier‐transport modeling, and density functional modeling. Finally, electrostatic gate‐defined quantum confinement is demonstrated using a scalable approach of large‐area CVD‐grown bilayer WS2 and ALD‐grown HfO2. The high dielectric constant and low leakage current enabled by HfO2 allows an estimated quantum dot size as small as 58 nm. The ability to lithographically define increasingly smaller devices is especially important for transition metal dichalcogenides due to their large effective masses, and should pave the way toward their use in quantum information processing applications.
Electrostatically defined quantum confinement in large‐area chemical vapor deposition‐grown 2D WS2 with HfO2 dielectrics grown by atomic layer deposition is reported. This marks a key milestone in scalable approaches toward 2D‐semiconductor‐based quantum devices, which has hitherto only been demonstrated with micrometer‐sized exfoliated flakes. The measurements show that low‐temperature carrier mobility is not charge impurity limited as commonly thought, but is due to another important but commonly overlooked factor: interface roughness.
Interferons (IFNs) are important in controlling the innate immune response to viral infections. Besides that, studies have found that IFNs also have antimicrobial, antiproliferative/antitumor and ...immunomodulatory effects. IFNs are divided into Type I, II and III. Type I IFNs, in particular IFN-α, is an approved treatment for hepatitis C. However, patients developed neuropsychological disorders during treatment. IFN-α induces proinflammatory cytokines, indoleamine 2,3-dioxygenase (IDO), oxidative and nitrative stress that intensifies the body's inflammatory response in the treatment of chronic inflammatory disease. The severity of the immune response is related to behavioral changes in both animal models and humans. Reactive oxygen species (ROS) is important for synaptic plasticity and long-term potentiation (LTP) in the hippocampus. However, excess ROS will generate highly reactive free radicals which may lead to neuronal damage and neurodegeneration. The limbic system regulates memory and emotional response, damage of neurons in this region is correlated with mood disorders. Due to the drawbacks of the treatment, often patients will not complete the treatment sessions, and this affects their recovery process. However, with proper management, this could be avoided. This review briefly describes the different types of IFNs and its pharmacological and clinical usages and a focus on IFN-α and its implications on depression.
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