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The Role of Microglia in Neurological Disorders
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The Role of Microglia in Neurological Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 4346

Special Issue Editor

Prof. Dr. Masashi Tanaka

E-Mail Website
Guest Editor
Department of Physical Therapy, Health Science University, 7187 Kodachi, Fujikawaguchiko-machi, Minamitsuru-gun, Yamanashi 401-0380, Japan
Interests: amyloid-beta; dementia; type 2 diabetes; innate immune system; inflammation; microglia; obesity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Microglia are innate immune cells that exhibit various functions in the central nervous system (CNS). The phagocytosis of cell debris, apoptotic cells, and cytotoxic factors (e.g., amyloid-β) contributes to CNS integrity, and interactions with neurons affect neuronal functions, such as synaptic plasticity. Therefore, microglial dysfunction has been reported to be closely implicated in the pathogenesis of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis; however, the mechanistic details remain unclear. Growing evidence has further shown that neuroinflammation by activated microglia exacerbates the pathologies of these disorders. Moreover, recent studies reported that microglial phenotypes are influenced by various factors, such as aging, gut microbiota, and metabolic diseases. These findings highlight microglia as an effective therapeutic target to prevent and improve neurological disorders.

This Special Issue aims to provide novel insights into the underlying mechanisms and/or therapeutic strategies for neurological disorders in terms of microglial functions. We welcome original articles, reviews, and commentaries that cover all aspects of this research topic.

Prof. Dr. Masashi Tanaka
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • inflammation
  • microglia
  • multiple sclerosis
  • neurodegenerative diseases
  • neurological disorders
  • neuron
  • Parkinson’s disease
  • phagocytosis

Published Papers (4 papers)

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Research

17 pages, 9367 KiB  
Article
Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures
by Debashis Dutta, Jianuo Liu, Enquan Xu and Huangui Xiong
Int. J. Mol. Sci. 2024, 25(7), 3588; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25073588 - 22 Mar 2024
Viewed by 595
Abstract
Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HANDs) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms underlying HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 [...] Read more.
Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HANDs) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms underlying HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 (gp120), a potent neurotoxin, plays a pivotal role in HAND pathogenesis. Methamphetamine (Meth) abuse exacerbates HANDs, but how this occurs is not fully understood. We hypothesize that Meth exacerbates HANDs by enhancing gp120-mediated neuroinflammation. To test this hypothesis, we studied the effect of Meth on gp120-induced microglial activation and the resultant production of proinflammatory cytokines in primary rat microglial cultures. Our results show that Meth enhanced gp120-induced microglial activation, as revealed by immunostaining and Iba-1 expression, and potentiated gp120-mediated NLRP3 expression and IL-1β processing and release, as assayed by immunoblotting and ELISA. Meth also augmented the co-localization of NLRP3 and caspase-1, increased the numbers of NLRP3 puncta and ROS production, increased the levels of iNOS expression and NO production, and increased the levels of cleaved gasderminD (GSDMD-N; an executor of pyroptosis) in gp120-primed microglia. The Meth-associated effects were attenuated or blocked by MCC950, an NLRP3 inhibitor, or Mito-TEMPO, a mitochondrial superoxide scavenger. These results suggest that Meth enhances gp120-associated microglial NLRP3 activation and the resultant proinflammatory responses via mitochondria-dependent signaling. Full article
(This article belongs to the Special Issue The Role of Microglia in Neurological Disorders)
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16 pages, 3206 KiB  
Article
Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome
by Álvaro Fernández-Blanco, Cèsar Sierra, Clara Tejido and Mara Dierssen
Int. J. Mol. Sci. 2024, 25(6), 3289; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063289 - 14 Mar 2024
Viewed by 619
Abstract
Research on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential intermediate states. [...] Read more.
Research on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential intermediate states. Indeed, recent work on microglial cells in young DS brains indicated that those evolve through different intermediate activation phenotypes before reaching a fully activated state. Here we used single nucleus RNA sequencing, to examine how trisomy affects microglial states in the Ts65Dn mouse model of DS. Despite no substantial changes in the proportion of glial populations, differential expression analysis revealed cell type-specific gene expression changes, most notably in astroglia, microglia, and oligodendroglia. Focusing on microglia, we identified differential expression of genes associated with different microglial states, including disease-associated microglia (DAMs), activated response microglia (ARMs), and human Alzheimer’s disease microglia (HAMs), in trisomic microglia. Furthermore, pseudotime analysis reveals a unique reactivity profile in Ts65Dn microglia, with fewer in a homeostatic state and more in an intermediate aberrantly reactive state than in euploid microglia. This comprehensive understanding of microglial transcriptional dynamics sheds light on potential pathogenetic mechanisms but also possible avenues for therapy for neurodevelopmental disorders. Full article
(This article belongs to the Special Issue The Role of Microglia in Neurological Disorders)
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12 pages, 8971 KiB  
Article
The Preventive Effect of Urinary Trypsin Inhibitor on Postoperative Cognitive Dysfunction, on the Aspect of Behavior, Evaluated by Y-Maze Test, via Modulation of Microglial Activity
by Eun-Hwa Cho, Chi-Bum In, Gyu-Won Lee, Seung-Wan Hong, Eun-Hye Seo, Won Hyung Lee and Seong-Hyop Kim
Int. J. Mol. Sci. 2024, 25(5), 2708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25052708 - 26 Feb 2024
Viewed by 579
Abstract
This experimental study was designed to evaluate the effect of ulinastatin, a urinary trypsin inhibitor, on postoperative cognitive dysfunction (POCD) in rats under general anesthesia with isoflurane, on the aspect of behavior, as evaluated using a Y-maze test and focusing on microglial activity. [...] Read more.
This experimental study was designed to evaluate the effect of ulinastatin, a urinary trypsin inhibitor, on postoperative cognitive dysfunction (POCD) in rats under general anesthesia with isoflurane, on the aspect of behavior, as evaluated using a Y-maze test and focusing on microglial activity. Ulinastatin (50,000 U/mL) and normal saline (1 mL) were randomly (1:1) administered intraperitoneally to the ulinastatin and control groups, respectively, before general anesthesia. Anesthesia with isoflurane 1.5 volume% was maintained for 2 h. The Y-maze test was used to evaluate cognitive function. Neuronal damage using caspase-1 expression, the degree of inflammation through cytokine detection, and microglial activation with differentiation of the phenotypic expression were evaluated. Twelve rats were enrolled in the study and evenly allocated into the two groups, with no dropouts from the study. The Y-maze test showed similar results in the two groups before general anesthesia (63 ± 12% in the control group vs. 64 ± 12% in the ulinastatin group, p = 0.81). However, a significant difference was observed between the two groups after general anesthesia (17 ± 24% in the control group vs. 60 ± 12% in the ulinastatin group, p = 0.006). The ulinastatin group showed significantly lower expression of caspase-1. Pro-inflammatory cytokine levels were significantly lower in the ulinastatin group than in the control group. The ulinastatin group had a significantly lower microglial activation (41.74 ± 10.56% in the control group vs. 4.77 ± 0.56% in the ulinastatin, p < 0.001), with a significantly lower activation of M1 phenotypes (52.19 ± 7.83% in the control group vs. 5.58 ± 0.76% in the ulinastatin group, p < 0.001). Administering ulinastatin before general anesthesia prevented neuronal damage and cognitive decline after general anesthesia, in terms of the aspect of behavior, as evaluated by the Y-maze test. The protective effect of ulinastatin was associated with the inhibition of microglial activation, especially the M1 phenotype. Full article
(This article belongs to the Special Issue The Role of Microglia in Neurological Disorders)
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15 pages, 2293 KiB  
Article
Cholesterol, Amyloid Beta, Fructose, and LPS Influence ROS and ATP Concentrations and the Phagocytic Capacity of HMC3 Human Microglia Cell Line
by Oscar M. Muñoz Herrera, Brian V. Hong, Ulises Ruiz Mendiola, Izumi Maezawa, Lee-Way Jin, Carlito B. Lebrilla, Danielle J. Harvey and Angela M. Zivkovic
Int. J. Mol. Sci. 2023, 24(12), 10396; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210396 - 20 Jun 2023
Cited by 1 | Viewed by 1978
Abstract
Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer’s disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of [...] Read more.
Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer’s disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of AD. High-throughput in vitro models to screen molecules for their effectiveness in reversing the pathogenic, pro-inflammatory microglia phenotype are needed. In this study, we used a multi-stimulant approach to test the usefulness of the human microglia cell 3 (HMC3) cell line, immortalized from a human fetal brain-derived primary microglia culture, in duplicating critical aspects of the dysfunctional microglia phenotype. HMC3 microglia were treated with cholesterol (Chol), amyloid beta oligomers (AβO), lipopolysaccharide (LPS), and fructose individually and in combination. HMC3 microglia demonstrated changes in morphology consistent with activation when treated with the combination of Chol + AβO + fructose + LPS. Multiple treatments increased the cellular content of Chol and cholesteryl esters (CE), but only the combination treatment of Chol + AβO + fructose + LPS increased mitochondrial Chol content. Microglia treated with combinations containing Chol + AβO had lower apolipoprotein E (ApoE) secretion, with the combination of Chol + AβO + fructose + LPS having the strongest effect. Combination treatment with Chol + AβO + fructose + LPS also induced APOE and TNF-α expression, reduced ATP production, increased reactive oxygen species (ROS) concentration, and reduced phagocytosis events. These findings suggest that HMC3 microglia treated with the combination of Chol + AβO + fructose + LPS may be a useful high-throughput screening model amenable to testing on 96-well plates to test potential therapeutics to improve microglial function in the context of AD. Full article
(This article belongs to the Special Issue The Role of Microglia in Neurological Disorders)
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