bims-microg 2024-10-06 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024‒10‒06
thirty-one papers selected by
Marcus Karlstetter, Universität zu Köln

NPC1 links cholesterol trafficking to microglial morphology via the gastrosome.
Neuroinflammation as a cause of differential Müller cell regenerative responses to retinal injury.
Modulation of diabetes-related retinal pathophysiology by PTX3.
Reactive microglia partially envelop viable neurons in prion diseases.
Tracking changes in functionality and morphology of repopulated microglia in young and old mice.
AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer's disease.
Knockdown of microglial iron import gene, Slc11a2, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer's disease.
Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.
Microglia-mediated neuron death requires TNF and is exacerbated by mutant Huntingtin.
Novel microglial transcriptional signatures promote social and cognitive deficits following repeated social defeat.
Loss of microglial Arid1a exacerbates microglial scar formation via elevated CCL5 after traumatic brain injury.
The intricate interplay between microglia and adult neurogenesis in Alzheimer's disease.
Irisin Alleviates Autoimmune Uveitis Through Promoting Retinal Microglial M1 to M2 Phenotypic Polarization Mediated by HIF-1α Pathway.
From Organotypic Mouse Brain Slices to Human Alzheimer Plasma Biomarkers: A Focus on Microglia.
Exercise training upregulates CD55 to suppress complement-mediated synaptic phagocytosis in Parkinson's disease.
The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease.
Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.
Abstinence from cocaine self-administration promotes microglia pruning of astrocytes which drives cocaine-seeking behavior.
Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.
Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.
Comparative evaluation of cigarette smoke and a heated tobacco product on microglial toxicity, oxidative stress and inflammatory response.
Monocyte invasion into the retina restricts the regeneration of neurons from Müller glia.
Salidroside improves blood-brain barrier integrity and cognitive function in hypobaric hypoxia mice by inhibiting microglia activation through GSK3β.
The mechanism and consequences of amyloid-β modulating thiamine pyrophosphokinase-1 expression in microglia.
Generation of an inducible destabilized-domain Cre mouse line to target disease associated microglia.
Role of copper during microglial inflammation.
Microglial CR3 promotes neuron ferroptosis via NOX2-mediated iron deposition in rotenone-induced experimental models of Parkinson's disease.
Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one downregulation of Galectin-3 ameliorates Aβ pathogenesis-induced neuroinflammation in 5 × FAD mice.
Fish microglia: Beyond the resident macrophages of the central nervous system - A review of their morphofunctional characteristics.
Role of Microglia in Central Nervous System Development and Plasticity.
Therapeutic approaches to microglial dysfunction in Alzheimer's disease: Enhancing phagocytosis and metabolic regulation.

Nat Commun. 2024 Oct 05. 15(1): 8638

NPC1 links cholesterol trafficking to microglial morphology via the gastrosome.

Joanna Zareba, Elena F Cattaneo, Ambra Villani, Alaa Othman, Sebastian Streb, Francesca Peri.

Microglia play important roles in brain development and homeostasis by removing dying neurons through efferocytosis. Morphological changes in microglia are hallmarks of many neurodegenerative conditions, such as Niemann-Pick disease type C. Here, NPC1 loss causes microglia to shift from a branched to an ameboid form, though the cellular basis and functional impact of this change remain unclear. Using zebrafish, we show that NPC1 deficiency causes an efferocytosis-dependent expansion of the microglial gastrosome, a collection point for engulfed material. In vivo and in vitro experiments on microglia and mammalian macrophages demonstrate that NPC1 localizes to the gastrosome, and its absence leads to cholesterol accumulation in this compartment. NPC1 loss and neuronal cell death synergistically affect gastrosome size and cell shape, increasing the sensitivity of NPC1-deficient cells to neuronal cell death. Finally, we demonstrate conservation of cholesterol accumulation and gastrosome expansion in NPC patient-derived fibroblasts, offering an interesting target for further disease investigation.

DOI: https://doi.org/10.1038/s41467-024-52874-6
Sci Adv. 2024 Oct 04. 10(40): eadp7916

Neuroinflammation as a cause of differential Müller cell regenerative responses to retinal injury.

Diana García-García, Lorena Vidal-Gil, Karine Parain, Jingxian Lun, Yann Audic, Albert Chesneau, Léa Siron, Demi Van Westendorp, Sophie Lourdel, Xavier Sánchez-Sáez, Despoina Kazani, Julien Ricard, Solène Pottin, Alicia Donval, Odile Bronchain, Morgane Locker, Jérôme E Roger, Caroline Borday, Patrick Pla, Juliette Bitard, Muriel Perron.

Unlike mammals, some nonmammalian species recruit Müller glia for retinal regeneration after injury. Identifying the underlying mechanisms may help to foresee regenerative medicine strategies. Using a Xenopus model of retinitis pigmentosa, we found that Müller cells actively proliferate upon photoreceptor degeneration in old tadpoles but not in younger ones. Differences in the inflammatory microenvironment emerged as an explanation for such stage dependency. Functional analyses revealed that enhancing neuroinflammation is sufficient to trigger Müller cell proliferation, not only in young tadpoles but also in mice. In addition, we showed that microglia are absolutely required for the response of mouse Müller cells to mitogenic factors while negatively affecting their neurogenic potential. However, both cell cycle reentry and neurogenic gene expression are allowed when applying sequential pro- and anti-inflammatory treatments. This reveals that inflammation benefits Müller glia proliferation in both regenerative and nonregenerative vertebrates and highlights the importance of sequential inflammatory modulation to create a regenerative permissive microenvironment.

DOI: https://doi.org/10.1126/sciadv.adp7916
Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2320034121

Modulation of diabetes-related retinal pathophysiology by PTX3.

Varun Pathak, Pietro M Bertelli, Edoardo Pedrini, Kevin Harkin, Elisa Peixoto, Lynsey-Dawn Allen, Kiran Mcloughlin, Natasha D Chavda, Kevin J Hamill, Jasenka Guduric-Fuchs, Antonio Inforzato, Barbara Bottazzi, Alan W Stitt, Reinhold J Medina.

  Diabetic retinopathy (DR) is a common complication of diabetes characterized by vascular pathology and neuroinflammation. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule that functions at the crossroads between innate immunity, inflammation, and tissue remodeling. DR is known to involve inflammatory pathways, although the potential relevance of PTX3 has not been explored. We found that PTX3 protein levels increased in the retina of diabetic mice. Similarly, evaluation of a publicly available transcriptomic human dataset revealed increased PTX3 expression in DR with diabetic macular edema and proliferative retinopathy, when compared to nondiabetic retinas or diabetic retinas without complications. To further understand the role of PTX3 within DR, we employed the streptozotocin-induced diabetes model in PTX3 knockout mice (PTX3KO), which were followed up for 9 mo to evaluate hallmarks of disease progression. In diabetic PTX3KO mice, we observed decreased reactive gliosis, diminished microglia activation, and reduced vasodegeneration, when compared to diabetic PTX3 wild-type littermates. The decrease in DR-associated pathological features in PTX3KO retinas translated into preserved visual function, as evidenced by improved optokinetic response, restored b-wave amplitude in electroretinograms, and attenuated neurodegeneration. We showed that PTX3 induced an inflammatory phenotype in human retinal macroglia, characterized by GFAP upregulation and increased secretion of IL6 and PAI-1. We confirmed that PTX3 was required for TNF-α-induced reactive gliosis, as PTX3KO retinal explants did not up-regulate GFAP in response to TNF-α. This study reveals a unique role for PTX3 as an enhancer of sterile inflammation in DR, which drives pathogenesis and ultimately visual impairment.

Keywords:  PTX3; diabetic retinopathy; gliosis; microglia; retinopathy

DOI:  https://doi.org/10.1073/pnas.2320034121
J Clin Invest. 2024 Oct 03. pii: e181169. [Epub ahead of print]

Reactive microglia partially envelop viable neurons in prion diseases.

Natallia Makarava, Tarek Safadi, Olga Bocharova, Olga Mychko, Narayan P Pandit, Kara Molesworth, Simone Baiardi, Li Zhang, Piero Parchi, Ilia V Baskakov.

  Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrated that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, a critical shift occured in microglial activity during the late preclinical stage, transitioning from PrPSc uptake to establishing extensive neuron-microglia body-to-body cell contacts. This change was followed by a rapid accumulation of PrPSc in the brain. Microglia that enveloped neurons exhibited hypertrophic, cathepsin D-positive lysosomal compartments. However, most neurons undergoing envelopment were only partially encircled by microglia. Despite up to 40% of cortical neurons being partially enveloped at clinical stages, only a small percentage of envelopment proceeded to full engulfment. Partially enveloped neurons lacked apoptotic markers but showed signs of functional decline. Neuronal envelopment was independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. This phenomenon of partial envelopment was consistently observed across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial envelopment of neurons by reactive microglia in the context of an actual neurodegenerative disease, not a disease model.

Keywords:  Infectious disease; Innate immunity; Neurodegeneration; Neuroscience; Prions

DOI:  https://doi.org/10.1172/JCI181169
J Neuroinflammation. 2024 Oct 03. 21(1): 248

Tracking changes in functionality and morphology of repopulated microglia in young and old mice.

Zuzanna M Luczak-Sobotkowska, Patrycja Rosa, Maria Banqueri Lopez, Natalia Ochocka, Anna Kiryk, Anna M Lenkiewicz, Martin Furhmann, Aleksander Jankowski, Bozena Kaminska.

  BACKGROUND: Microglia (MG) are myeloid cells of the central nervous system that support homeostasis and instigate neuroinflammation in pathologies. Single-cell RNA sequencing (scRNA-seq) revealed the functional heterogeneity of MG in mouse brains. Microglia are self-renewing cells and inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling depletes microglia which rapidly repopulate. The functions of repopulated microglia are poorly known.METHODS: We combined scRNA-seq, bulk RNA-seq, immunofluorescence, and confocal imaging to study the functionalities and morphology of repopulated microglia.
RESULTS: A CSRF1R inhibitor (BLZ-945) depleted microglia within 21 days and a number of microglia was fully restored within 7 days, as confirmed by TMEM119 staining and flow cytometry. ScRNA-seq and computational analyses demonstrate that repopulated microglia originated from preexisting progenitors and reconstituted functional clusters but upregulated inflammatory genes. Percentages of proliferating, immature microglia displaying inflammatory gene expression increased in aging mice. Morphometric analysis of MG cell body and branching revealed a distinct morphology of repopulated MG, particularly in brains of old mice. We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences may contribute to the deterioration of MG protective functions with age.

Keywords:  Aging; CSF1R inhibitors; Microglia repopulation; Microglial heterogeneity; ScRNA-seq; Transcriptomics

DOI:  https://doi.org/10.1186/s12974-024-03242-0
J Neuroinflammation. 2024 Sep 28. 21(1): 245

AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer's disease.

Yi Sak Kim, Soo-Ho Choi, Keun-Young Kim, Juliana M Navia-Pelaez, Guy A Perkins, Seunghwan Choi, Jungsu Kim, Nicolaus Nazarenkov, Robert A Rissman, Won-Kyu Ju, Mark H Ellisman, Yury I Miller.

  Microglia-driven neuroinflammation plays an important role in the development of Alzheimer's disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/-APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimer's disease associated oxidative stress and neurodegeneration.

Keywords:  AIBP; Alzheimer’s disease; Inflammaraft; Lipid rafts; Microglia; Mitochondria; Neuroinflammation; Oxidative stress; TLR4

DOI:  https://doi.org/10.1186/s12974-024-03214-4
J Neuroinflammation. 2024 Sep 27. 21(1): 238

Knockdown of microglial iron import gene, Slc11a2, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer's disease.

Katrina Volk Robertson, Alec S Rodriguez, Jean-Philippe Cartailler, Shristi Shrestha, Michael W Schleh, Kyle R Schroeder, Arianna M Valenti, Alec T Kramer, Fiona E Harrison, Alyssa H Hasty.

  BACKGROUND: Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype.METHODS: In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre-ERT2;Slc11a2flfl;APP/PS1+or - mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted.
RESULTS: DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers associated with subsets of disease-associated microglia (DAMs), such as Apoe, Ctsb, Ly9, Csf1, and Hif1α.
CONCLUSIONS: This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2KD APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

Keywords:  APP/PS1; Alzheimer’s disease; Behavior; DMT1; Inflammation; Iron; Microglia; Neuroinflammation; Sex differences; Slc11a2

DOI:  https://doi.org/10.1186/s12974-024-03238-w
Neuron. 2024 Sep 24. pii: S0896-6273(24)00654-8. [Epub ahead of print]

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

Gillian K Carling, Li Fan, Nessa R Foxe, Kendra Norman, Man Ying Wong, Daphne Zhu, Carlo Corona, Agnese Razzoli, Fangmin Yu, Allan Yarahmady, Pearly Ye, Hao Chen, Yige Huang, Sadaf Amin, Rebecca Sereda, Chloe Lopez-Lee, Emmanouil Zacharioudakis, Xiaoying Chen, Jielin Xu, Feixiong Cheng, Evripidis Gavathiotis, Ana Maria Cuervo, David M Holtzman, Sue-Ann Mok, Subhash C Sinha, Simone Sidoli, Rajiv R Ratan, Wenjie Luo, Shiaoching Gong, Li Gan.

  The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

Keywords:  APOE; Alzheimer’s disease; R47H; TREM2; cGAS; inflammation; interferon; microglia; senescence; tau

DOI:  https://doi.org/10.1016/j.neuron.2024.09.006
Pharmacol Res. 2024 Oct 01. pii: S1043-6618(24)00388-8. [Epub ahead of print] 107443

Microglia-mediated neuron death requires TNF and is exacerbated by mutant Huntingtin.

Alexander P Young, Eileen M Denovan-Wright.

  Microglia, the resident immune cells of the brain, regulate the balance of inflammation in the central nervous system under healthy and pathogenic conditions. Huntington's disease (HD) is a chronic neurodegenerative disease characterized by activated microglia and elevated concentrations of pro-inflammatory cytokines within the brain. Chronic hyperactivation of microglia is associated with brain pathology and eventual neuron death. However, it is unclear which specific cytokines are required for neuron death and whether HD neurons may be hypersensitive to neuroinflammation. We assessed the profile of microglia-secreted proteins in response to LPS and IFNγ, and a conditioned media paradigm was used to examine the effects of these secreted proteins on cultured neuronal cells. STHdhQ7/Q7 and STHdhQ111/Q111 neuronal cells were used to model wild-type and HD neurons, respectively. We determined that STHdhQ111/Q111 cells were hypersensitive to pro-inflammatory factors secreted by microglia, and that TNF was to induce neuronal death. Microglia-mediated neuronal death could be effectively halted through the use of JAK-STAT or TNF inhibitors which supported the requirement for TNF as well as IFNγ in the process of secondary neurotoxicity. Further data derived from human HD patients as well as HD mice were suggestive of enhanced receptor density for TNF (TNFR1) and IFNγ (IFNGR) which could sensitize the HD brain to these cytokines. This highlights several potential mechanisms by which microglia may induce neuronal death and suggests that these mechanisms may be upregulated in the brain of HD patients.

Keywords:  Huntington’s disease; JAK-STAT; Microglia; TNF; cytokines; interferons; neuroinflammation

DOI:  https://doi.org/10.1016/j.phrs.2024.107443
Commun Biol. 2024 Sep 28. 7(1): 1199

Novel microglial transcriptional signatures promote social and cognitive deficits following repeated social defeat.

Ethan J Goodman, Damon J DiSabato, John F Sheridan, Jonathan P Godbout.

Chronic stress is associated with anxiety and cognitive impairment. Repeated social defeat (RSD) in mice induces anxiety-like behavior driven by microglia and the recruitment of inflammatory monocytes to the brain. Nonetheless, it is unclear how microglia communicate with other cells to modulate the physiological and behavioral responses to stress. Using single-cell (sc)RNAseq, we identify novel, to the best of our knowledge, stress-associated microglia in the hippocampus defined by RNA profiles of cytokine/chemokine signaling, cellular stress, and phagocytosis. Microglia depletion with a CSF1R antagonist (PLX5622) attenuates the stress-associated profile of leukocytes, endothelia, and astrocytes. Furthermore, RSD-induced social withdrawal and cognitive impairment are microglia-dependent, but social avoidance is microglia-independent. Furthermore, single-nuclei (sn)RNAseq shows robust responses to RSD in hippocampal neurons that are both microglia-dependent and independent. Notably, stress-induced CREB, oxytocin, and glutamatergic signaling in neurons are microglia-dependent. Collectively, these stress-associated microglia influence transcriptional profiles in the hippocampus related to social and cognitive deficits.

DOI: https://doi.org/10.1038/s42003-024-06898-9
Cell Commun Signal. 2024 Sep 30. 22(1): 467

Loss of microglial Arid1a exacerbates microglial scar formation via elevated CCL5 after traumatic brain injury.

Jin-Peng Ke, Bao-Dong He, Mao-Lei Gong, Zhong-Ze Yan, Hong-Zhen Du, Zhao-Qian Teng, Chang-Mei Liu.

  Traumatic brain injury (TBI) is an acquired insult to the brain caused by an external mechanical force, potentially resulting in temporary or permanent impairment. Microglia, the resident immune cells of the central nervous system, are activated in response to TBI, participating in tissue repair process. However, the underlying epigenetic mechanisms in microglia during TBI remain poorly understood. ARID1A (AT-Rich Interaction Domain 1 A), a pivotal subunit of the multi-protein SWI/SNF chromatin remodeling complex, has received little attention in microglia, especially in the context of brain injury. In this study, we generated a Arid1a cKO mouse line to investigate the potential roles of ARID1A in microglia in response to TBI. We found that glial scar formation was exacerbated due to increased microglial migration and a heightened inflammatory response in Arid1a cKO mice following TBI. Mechanistically, loss of ARID1A led to an up-regulation of the chemokine CCL5 in microglia upon the injury, while the CCL5-neutralizing antibody reduced migration and inflammatory response of LPS-stimulated Arid1a cKO microglia. Importantly, administration of auraptene (AUR), an inhibitor of CCL5, repressed the microglial migration and inflammatory response, as well as the glial scar formation after TBI. These findings suggest that ARID1A is critical for microglial response to injury and that AUR has a therapeutic potential for the treatment of TBI.

Keywords:   Arid1a ; Ccl5 ; Inflammation; Microglia; Migration; TBI

DOI:  https://doi.org/10.1186/s12964-024-01852-y
Front Cell Neurosci. 2024 ;18 1456253

The intricate interplay between microglia and adult neurogenesis in Alzheimer's disease.

Iris Früholz, Melanie Meyer-Luehmann.

  Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions.

Keywords:  Alzheimer’s disease; adult neurogenesis; amyloid plaques; microglia; neurodegeneration

DOI:  https://doi.org/10.3389/fncel.2024.1456253
Inflammation. 2024 Sep 29.

Irisin Alleviates Autoimmune Uveitis Through Promoting Retinal Microglial M1 to M2 Phenotypic Polarization Mediated by HIF-1α Pathway.

Meiqi Wang, Xue Huang, Jia Shu, Hongxi Li, Tao Yang, Na Li, Peizeng Yang.

  Irisin, proteolytically cleaved from Fndc5 protein, has been identified as an exercise-related hormone. Here, we investigated the irisin levels in aqueous humor and its involvement in the pathogenesis of uveitis. The results revealed that the irisin level in the aqueous humor was significantly decreased in Vogt-Koyanagi-Harada (VKH), and Behcet uveitis (BU) patients, and was negatively correlated with TNF-α in BU patients. Exogenous supplementation of irisin alleviated scores of experimental autoimmune uveitis (EAU) clinically and pathologically and suppressed the proportion of Th1 and Th17 cells in spleen. Fndc5-/- EAU mice exhibited more severe inflammatory manifestations with increased microglial activation in the retina. Irisin could mitigate M1 microglia and promote M2 microglia polarization. RNA sequencing of the retina showed that HIF-1α pathway was significantly enriched in Fndc5-/- EAU mice. HIF-1α pathway inhibitor significantly rescued EAU severity, associated with a decreased M1 microglial polarization in the retina of Fndc5-/- mice. In conclusion, we highlighted that irisin could alleviate uveitis by inhibiting Th1 and Th17 cells and reducing M1 microglial polarization via HIF-1α pathway.

Keywords:  HIF-1α pathway; irisin; iveitis; microglia

DOI:  https://doi.org/10.1007/s10753-024-02149-5
Biomolecules. 2024 Sep 03. pii: 1109. [Epub ahead of print]14(9):

From Organotypic Mouse Brain Slices to Human Alzheimer Plasma Biomarkers: A Focus on Microglia.

Katharina Steiner, Sakir Necat Yilmaz, Alessa Gern, Josef Marksteiner, Klaus Faserl, Mathias Villunger, Bettina Sarg, Christian Humpel.

  Alzheimer's disease is a severe neurodegenerative disorder, and the discovery of biomarkers is crucial for early diagnosis. While the analysis of biomarkers in cerebrospinal fluid is well accepted, there are currently no blood biomarkers available. Our research focuses on identifying novel plasma biomarkers for Alzheimer's disease. To achieve this, we employed a technique that involves coupling human plasma to mouse organotypic brain slices via microcontact prints. After culturing for two weeks, we assessed Iba1-immunopositive microglia on these microcontact prints. We hypothesized that plasma from Alzheimer's patients contains factors that affect microglial migration. Our data indicated that plasma from Alzheimer's patients significantly inhibited the migration of round Iba1-immunoreactive microglia (13 ± 3, n = 24, p = 0.01) compared to healthy controls (50 ± 16, n = 23). Based on these findings, we selected the most promising plasma samples and conducted mass spectrometry using a differential approach, and we identified four potential biomarkers: mannose-binding protein C, macrophage receptor MARCO, complement factor H-related protein-3, and C-reactive protein. Our method represents a novel and innovative approach to translate research findings from mouse models to human applications.

Keywords:  Alzheimer’s disease; biomarker; mass spectrometry; microcontact printing; microglia; organotypic brain slice; plasma

DOI:  https://doi.org/10.3390/biom14091109
J Neuroinflammation. 2024 Sep 28. 21(1): 246

Exercise training upregulates CD55 to suppress complement-mediated synaptic phagocytosis in Parkinson's disease.

Hongkai Yao, Weifang Tong, Yunping Song, Ruoyu Li, Xuerui Xiang, Wen Cheng, Yunjiao Zhou, Yijing He, Yi Yang, Yunxi Liu, Siguang Li, Lingjing Jin.

  The primary pathological change in Parkinson's disease (PD) is the progressive degeneration of dopaminergic neurons in the substantia nigra. Additionally, excessive microglial activation and synaptic loss are also typical features observed in PD samples. Exercise trainings have been proven to improve PD symptoms, delay the disease progression as well as affect excessive microglial synaptic phagocytosis. In this study, we established a mouse model of PD by injecting mouse-derived α-synuclein preformed fibrils (M-α-syn PFFs) into the substantia nigra, and demonstrated that treadmill exercise inhibits microglial activation and synaptic phagocytosis in striatum. Using RNA-Seq and proteomics, we also found that PD involves excessive activation of the complement pathway which is closely related to over-activation of microglia and abnormal synaptic function. More importantly, exercise training can inhibit complement levels and complement-mediated microglial phagocytosis of synapses. It is probably triggered by CD55, as we observed that CD55 in the striatum significantly increased after exercise training and up-regulation of that molecule rescued motor deficits of PD mice, accompanied with reduced microglial synaptic phagocytosis in the striatum. This research elucidated the interplay among microglia, complement, and synapses, and analyzed the effects of exercise training on these factors. Our work also suggested CD55 as a complement-relevant candidate molecule for developing therapeutic strategies of PD.

Keywords:  CD55; Complement pathway; Microglia; Parkinson’s disease; Proteomics and RNA-seq analysis; Synapses

DOI:  https://doi.org/10.1186/s12974-024-03234-0
Neural Regen Res. 2025 Aug 01. 20(8): 2361-2372

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease.

Shengyang Zhou, Ting Li, Wei Zhang, Jian Wu, Hui Hong, Wei Quan, Xinyu Qiao, Chun Cui, Chenmeng Qiao, Weijiang Zhao, Yanqin Shen.

JOURNAL/nrgr/04.03/01300535-202508000-00026/figure1/v/2024-09-30T120553Z/r/image-tiff Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-01684
J Neuroinflammation. 2024 Sep 27. 21(1): 240

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.

Valerie Joers, Benjamin C Murray, Caroline McLaughlin, Danielle Oliver, Hannah E Staley, Jazmyn Coronado, Cindy Achat-Mendes, Sanam Golshani, Sean D Kelly, Matthew Goodson, Danica Lee, Fredric P Manfredsson, Bob M Moore Ii, Malú Gámez Tansey.

  Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) Asyn in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

Keywords:  Alpha-synuclein; Cannabinoid receptor-2; Microglia phenotype; Parkinson’s disease

DOI:  https://doi.org/10.1186/s12974-024-03221-5
bioRxiv. 2024 Sep 21. pii: 2024.09.20.614128. [Epub ahead of print]

Abstinence from cocaine self-administration promotes microglia pruning of astrocytes which drives cocaine-seeking behavior.

Anze Testen, Jonathan W VanRyzin, Tania J Bellinger, Ronald Kim, Han Wang, Matthew J Gastinger, Emily A Witt, Janay P Franklin, Haley A Vecchiarelli, Katherine Picard, Marie-Ève Tremblay, Kathryn J Reissner.

Rodent drug self-administration leads to compromised ability of astrocytes to maintain glutamate homeostasis within the brain's reward circuitry, as well as reductions in surface area, volume, and synaptic colocalization of astrocyte membranes. However, the mechanisms driving astrocyte responses to cocaine are unknown. Here, we report that long-access cocaine self-administration followed by prolonged home cage abstinence results in decreased branching complexity of nucleus accumbens astrocytes, characterized by the loss of peripheral processes. Using a combination of confocal fluorescence microcopy and immuno-gold electron microscopy, we show that alterations in astrocyte structural features are driven by microglia phagocytosis, as labeled astrocyte membranes are found within microglia phagolysosomes. Inhibition of complement C3-mediated phagocytosis using the neutrophil inhibitory peptide (NIF) rescued astrocyte structure and decreased cocaine seeking behavior following cocaine self-administration and abstinence. Collectively, these results provide evidence for microglia pruning of accumbens astrocytes across cocaine abstinence which mediates cocaine craving.

DOI: https://doi.org/10.1101/2024.09.20.614128
Neuroprotection. 2024 Sep;2(3): 182-195

Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.

Tobiloba Samuel Olajide, Toheeb O Oyerinde, Omolabake I Omotosho, Oritoke M Okeowo, Olayemi J Olajide, Omamuyouwi M Ijomone.

  The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.

Keywords:  aging; ferritin; microglia; neurodegenerative diseases; senescence-associated secretory phenotype; senescent

DOI:  https://doi.org/10.1002/nep3.56
J Clin Invest. 2024 Oct 01. pii: e178628. [Epub ahead of print]

Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.

Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen.

  Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent anti-tumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

Keywords:  Brain cancer; Cancer immunotherapy; Macrophages; Oncology

DOI:  https://doi.org/10.1172/JCI178628
J Transl Med. 2024 Sep 30. 22(1): 876

Comparative evaluation of cigarette smoke and a heated tobacco product on microglial toxicity, oxidative stress and inflammatory response.

Alfio Distefano, Laura Orlando, Konstantinos Partsinevelos, Lucia Longhitano, Rosalia Emma, Massimo Caruso, Nunzio Vicario, Simona Denaro, Ang Sun, Antonio Giordano, Barbara Tomasello, Amer M Alanazi, Giovanni Li Volti, Angela Maria Amorini.

  BACKGROUND: Tobacco smoking is the leading cause of preventable death and disease worldwide, with over 8 million annual deaths attributed to cigarette smoking. This study investigates the impact of cigarette smoke and heated tobacco products (HTPs) on microglial function, focusing on toxicological profiles, inflammatory responses, and oxidative stress using ISO standard and clinically relevant conditions of exposure.METHODS: We assessed cell viability, reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial function, unfolded protein response, and inflammation in human microglial cells (HMC3) exposed to cigarette smoke, HTP aerosol or nicotine.
RESULTS: Our findings show that cigarette smoke significantly reduces microglial viability, increases ROS formation, induces lipid peroxidation, and reduces intracellular glutathione levels. Cigarette smoke also alters the expression of genes involved in mitochondrial dynamics and biogenesis, leading to mitochondrial dysfunction. Additionally, cigarette smoke impairs the unfolded protein response, activates the NF-κB pathway, and induces a pro-inflammatory state characterized by increased TNF and IL-18 expression. Furthermore, cigarette smoke causes DNA damage and decreases the expression of the aging marker Klotho β. In contrast, HTP, exhibited a lesser degree of microglial toxicity, with reduced ROS production, lipid peroxidation, and mitochondrial dysfunction compared to conventional cigarettes.
CONCLUSION: These results highlight the differential toxicological profile of cigarette smoke and HTP on microglial cells, suggesting a potential harm reduction strategy for neurodegenerative disease for smokers unwilling or unable to quit.

Keywords:  Aging; Cigarette smoking; Heated tobacco product; Inflammation; Microglia; Nicotine; Oxidative stress; Toxicity

DOI:  https://doi.org/10.1186/s12967-024-05688-5
J Neurosci. 2024 Oct 01. pii: e0938242024. [Epub ahead of print]

Monocyte invasion into the retina restricts the regeneration of neurons from Müller glia.

Nicolai Blasdel, Sucheta Bhattacharya, Phoebe C Donaldson, Thomas A Reh, Levi Todd.

Endogenous reprogramming of glia into neurogenic progenitors holds great promise for neuron restoration therapies. Using lessons from regenerative species, we have developed strategies to stimulate mammalian Müller glia to regenerate neurons in vivo in the adult retina. We have demonstrated that the transcription factor Ascl1 can stimulate Müller glia neurogenesis. However, Ascl1 is only able to reprogram a subset of Müller glia into neurons. We have reported that neuroinflammation from microglia inhibits neurogenesis from Müller glia. Here we find that the peripheral immune response is a barrier to CNS regeneration. We show that monocytes from the peripheral immune system infiltrate the injured retina and negatively influence neurogenesis from Müller glia. Using CCR2-knockout mice of both sexes we find that preventing monocyte infiltration improves the neurogenic and proliferative capacity of Müller glia stimulated by Ascl1. Using scRNA-seq analysis we identified a signaling axis wherein Osteopontin, a cytokine highly expressed by infiltrating immune cells is sufficient to suppress mammalian neurogenesis. This work implicates the response of the peripheral immune system as a barrier to regenerative strategies of the retina.Significance Statement Regeneration of neurons in the central nervous system is extremely limited in mammals. Transgenic overexpression of the proneural transcription factor Ascl1 enables mammalian retinal glia to regenerate some neurons lost to injury. We found that during this regenerative response to injury, monocytes from the periphery invade the neural retina and these inflammatory cells negatively regulate the ability of Müller glia to reprogram into neurogenic progenitors. When monocytes are inhibited from infiltrating the retina, regeneration of neurons from Müller glia is significantly enhanced. This work implicates peripheral immunomodulation as a tool to enhance endogenous neuronal replacement strategies.

DOI: https://doi.org/10.1523/JNEUROSCI.0938-24.2024
Phytother Res. 2024 Oct 04.

Salidroside improves blood-brain barrier integrity and cognitive function in hypobaric hypoxia mice by inhibiting microglia activation through GSK3β.

Xianxie Zhang, Huiting Zhang, Zuoxu Liu, Tianke Huang, Ru Yi, Zengchun Ma, Yue Gao.

  Salidroside, an active component found in Rhodiola rosea L., has emerged as a potential therapeutic agent for the prevention and treatment of hypoxic brain injury, while the precise target and mechanism of salidroside were remain unclear. The study utilized techniques such as network pharmacology, transcriptome sequencing to investigate the mechanism and target of salidroside in regulating blood-brain barrier (BBB) function to protect hypoxic brain injury in vivo. Utilized macromolecular docking and molecular biology techniques to explore the molecular mechanism of salidroside in alleviating brain injury induced by hypoxia in BV2 cell model. The results show that salidroside alleviated the learning and memory dysfunction and pathological injury in mice exposed to hypobaric hypoxia, reduced brain water content and attenuate the inflammatory response and oxidative stress, effectively reversed S100β in serum and promoted the repair of BBB. GSK3β is an important therapeutic target of salidroside in the treatment of hypoxic cognitive impairment, and salidroside can specifically bind GSK3β in the ATP binding pocket, inducing the phosphorylation of GSK3β, targeting downstream Nrf-2 to regulate microglia activity, promoting the accumulation of β-catenin, thereby inhibiting microglial activation, improving the BBB integrity injury and achieving a neuroprotective effect. This study demonstrates that salidroside can inhibit the activation of microglia by inducing GSK3β phosphorylation, achieve neuroprotective effects and alleviate learning and memory dysfunction in hypobaric hypoxia mice. This study provides a theoretical basis for the development of salidroside and the clinical application of Rhodiola rosea L.

Keywords:  GSK3β; Salidroside; blood–brain barrier; hypobaric hypoxia brain injury; microglia

DOI:  https://doi.org/10.1002/ptr.8264
bioRxiv. 2024 Sep 19. pii: 2024.09.18.613405. [Epub ahead of print]

The mechanism and consequences of amyloid-β modulating thiamine pyrophosphokinase-1 expression in microglia.

Xiaoqin Cheng, Ruoqi Zhao, Hongyan Qiu, Peiwen Song, Lanwen Kou, Shaoming Sang, Yingfeng Xia, Wenwen Cai, Boru Jin, Qiang Huang, Peng Yuan, Chunjiu Zhong.

Ample studies attribute cognitive decline in Alzheimer's disease to amyloid-β deposition 1-6 . However, brain amyloid-β accumulation that saturates years before the manifestation of clinical symptoms is dissociated with cognitive decline of the disease 7 . It is unknown how these two processes are mechanistically linked. In this and our accompanied study, we report that thiamine pyrophosphokinase-1 (TPK) deficiency plays essential roles in both processes via distinct mechanisms. Here we describe that diminished microglia Tpk controls the propagation of amyloid-β plaques. In APP/PS1 transgenic mice, microglia showed elevated Tpk expression at 2-month-old, but reduction in a plaque-centric manner at 8-month-old. Interestingly, lipopolysaccharide, but not amyloid-β, induceed Tpk reduction in cultured microglia. Tpk reduction led to microglia dysfunction, showing volatile motility but reduced phagocytosis and weak response to focal tissue injury, with accumulation of intracellular lipid droplets and abnormal mitochrondria. In Alzheimer's disease mice, microglia-specific knockout of Tpk caused diminished plaque coverage, exacerbated plaque burden and synaptic loss. However, increased plaques were not accompanied by the development of neurofibrillary tangles or brain atrophy, in contrast to the phenotype described in our accompanied paper with neuronal Tpk deletion. In conclusion, plaque-induced inflammation reduces Tpk in microglia, selectively exacerbating the spread of amyloid pathology.

DOI: https://doi.org/10.1101/2024.09.18.613405
bioRxiv. 2024 Sep 19. pii: 2024.09.18.613773. [Epub ahead of print]

Generation of an inducible destabilized-domain Cre mouse line to target disease associated microglia.

Caden M Henningfield, Nellie Kwang, Kate Inman Tsourmas, Jonathan Neumann, Shimako Kawauchi, Vivek Swarup, Grant R MacGregor, Kim N Green.

The function of microglia during progression of Alzheimer's disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed a mouse strain that expresses destabilized-domain Cre recombinase (DD-Cre) from the Cst7 locus ( Cst7 DD-Cre ) and tested this in 5xFAD amyloidogenic, Ai14 tdTomato cre-reporter line mice. Dietary administration of trimethoprim to induce DD-Cre activity produces long-term labeling in disease associated microglia (DAM) without evidence of leakiness, with tdTomato-expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque-associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non-labeled PAMs. This model should allow inducible cre-loxP targeting of DAMs, without leakiness.Highlights: We developed a new mouse strain which specifically enables recombination of loxP sites in disease associated microglia (DAMs) and can be used to manipulate DAM-gene expression.DAMs represent a subset of plaque associated microglia (PAMs), and DAM expression increases with disease progression.Spatial transcriptomic analyses reveal that DAMs have higher expression of disease and inflammatory genes compared to other PAMs.

DOI: https://doi.org/10.1101/2024.09.18.613773
bioRxiv. 2024 Sep 19. pii: 2024.09.18.613750. [Epub ahead of print]

Role of copper during microglial inflammation.

Laura Craciun, Sandra E Muroy, Kaoru Saijo.

Copper plays crucial roles in various physiological functions of the nervous and immune systems. Dysregulation of copper homeostasis is linked to several diseases, including neurodegenerative diseases. Since dysfunctional microglial immunity can contribute to such diseases, we investigated the role of copper in microglial immunity. We found that both increased and decreased copper levels induced by chemical treatments suppresses lipopolysaccharide (LPS)-mediated inflammation in microglial cells, as determined by RT-qPCR analysis. RNA sequencing (RNA-seq) analysis confirmed that increased copper level reduces the inflammatory response to LPS; however, it also showed that decreased copper level affects genes involved in cell proliferation, transcription, and autophagosome regulation. These findings suggest that copper is vital for maintaining normal immune function in microglia, and both copper excess and deficiency can disrupt microglial immunity.

DOI: https://doi.org/10.1101/2024.09.18.613750
Redox Biol. 2024 Sep 24. pii: S2213-2317(24)00347-1. [Epub ahead of print]77 103369

Microglial CR3 promotes neuron ferroptosis via NOX2-mediated iron deposition in rotenone-induced experimental models of Parkinson's disease.

Qinghui Wang, Jianing Liu, Yu Zhang, Zhen Li, Zirui Zhao, Wanwei Jiang, Jie Zhao, Liyan Hou, Qingshan Wang.

  The activation of complement receptor 3 (CR3) in microglia contributes to neurodegeneration in neurological disorders, including Parkinson's disease (PD). However, it remains unclear for mechanistic knowledge on how CR3 mediates neuronal damage. In this study, the expression of CR3 and its ligands iC3b and ICAM-1 was found to be up-regulated in the midbrain of rotenone PD mice, which was associated with elevation of iron content and disruption of balance of iron metabolism proteins. Interestingly, genetic deletion of CR3 blunted iron accumulation and recovered the expression of iron metabolism markers in response to rotenone. Furthermore, reduced lipid peroxidation, ferroptosis of dopaminergic neurons and neuroinflammation were detected in rotenone-lesioned CR3-/- mice compared with WT mice. The regulatory effect of CR3 on ferroptotic death of dopaminergic neurons was also mirrored in vitro. Mechanistic study revealed that iron accumulation in neuron but not the physiological contact between microglia and neurons was essential for microglial CR3-regulated neuronal ferroptosis. In a cell-culture system, microglial CR3 silence significantly dampened iron deposition in neuron in response to rotenone, which was accompanied by mitigated lipid peroxidation and neurodegeneration. Furthermore, ROS released from activated microglia via NOX2 was identified to couple microglial CR3-mediated iron accumulation and subsequent neuronal ferroptosis. Finally, supplementation with exogenous iron was found to recover the sensitivity of CR3-/- mice to rotenone-induced neuronal ferroptosis. Altogether, our findings suggested that microglial CR3 regulates neuron ferroptosis through NOX2 -mediated iron accumulation in experimental Parkinsonism, providing novel points of the immunopathogenesis of neurological disorders.

Keywords:  CR3; Ferroptosis; Iron; Lipid peroxidation; Microglia; Parkinson's disease

DOI:  https://doi.org/10.1016/j.redox.2024.103369
Life Sci. 2024 Oct 01. pii: S0024-3205(24)00675-1. [Epub ahead of print] 123085

Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one downregulation of Galectin-3 ameliorates Aβ pathogenesis-induced neuroinflammation in 5 × FAD mice.

Xueyan Liu, Ping Chen, Wei Wu, Meihua Zhong, Shiyu Dong, Huiling Lin, Chaoxian Dai, Zhile Zhang, Shiqi Lin, Cuilan Che, Jiexin Xu, Chenlu Li, Hongwei Li, Xiaodong Pan, Zhou Chen, Xiaochun Chen, Zu-Cheng Ye.

  Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to a progressive synaptic loss and cognitive decline. Recent evidence highlights Galectin-3 (Gal-3) as a crucial factor in Aβ pathogenesis, yet effective strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study assesses the therapeutic efficacy of D30, an innovative anti-AD compound manifested promising effects on reducing Aβ deposition and alleviating neuronal damage in scopolamine-induced AD models. In our study, we administered neurotoxic oligomeric Aβ (oAβ) to mice and observed increased Gal-3 deposition and microglial activation in the hippocampus, leading to significant cognitive impairments. Similarly, in the 5 × FAD mouse model, known for Aβ overproduction, there was a progressive rise in Gal-3 levels and glial cell activation. We then investigated the effects of D30 on 5 × FAD mice, focusing on its modulation of Gal-3 and Aβ and impact on neuroinflammatory responses. D30 effectively reduced Aβ monomer production by inhibiting the expression of Amyloid Precursor Protein (APP) and presenilin 1 (PS1), as well as decreasing Aβ oligomer aggregation. Treatment with D30 not only improved cognitive functions but also reversed dendritic spine loss and increased PSD95 expression in 5 × FAD mice. Notably, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. Mechanistic studies revealed that D30 binds to Gal-3 and disrupts the interaction between Gal-3 and the triggering receptor expressed on myeloid cells 2 (TREM2), as confirmed by fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST). Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting neurons, D30 emerged as a novel compound with promising potential for AD treatment.AIMS: Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aβ pathogenesis. However, strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study evaluates the therapeutic efficacy of D30, in reducing Gal-3 and Aβ pathogenesis.
MATERIALS AND METHODS: We applied exogenous oligomeric Aβ and used 5 × FAD mice to assess the impact of Aβ on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST).
KEY FINDINGS: D30 effectively reduced Aβ monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aβ aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST.
SIGNIFICANCE: Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.

Keywords:  Alzheimer's disease; Galectin-3; Microglia; β-Amyloid

DOI:  https://doi.org/10.1016/j.lfs.2024.123085
Dev Comp Immunol. 2024 Sep 26. pii: S0145-305X(24)00146-0. [Epub ahead of print]162 105274

Fish microglia: Beyond the resident macrophages of the central nervous system - A review of their morphofunctional characteristics.

Jose Carlos Campos-Sánchez, José Meseguer, Francisco A Guardiola.

  From classical to modern literature on microglia, the importance of the potential and variability of these immune cells in vertebrates has been pointed out. Recent aspects such as relationships and interactions between microglia and neurons in both normal and injured neural tissues, as well as their nexus with other organs and with the microbiota, or how these cells are modulated during development and adulthood are current topics of major interest. State-of-the-art research methodologies, including microscopy and potent in vivo imaging techniques, genomic and proteomic methods, current culture conditions together with the easy maintenance and manipulation of some fish embryos and adult specimens such as zebrafish (Danio rerio), have emerged and adapted to the phylogenetic position of some fish species. Furthermore, these advancements have facilitated the development of successful protocols aimed at addressing significant hypotheses and unresolved questions regarding vertebrate glia. The present review aims to analyse the available information on fish microglia, mainly the most recent one concerning teleosts, to establish an overview of their structural and immune functional features as a basis for their potentialities, heterogeneity, diversification, involvement, and relationships with neurons under normal and pathological conditions.

Keywords:  Immune system; Microglia; Nervous system; Teleosts; Vertebrates

DOI:  https://doi.org/10.1016/j.dci.2024.105274
Cold Spring Harb Perspect Biol. 2024 Sep 30. pii: a041810. [Epub ahead of print]

Role of Microglia in Central Nervous System Development and Plasticity.

Dorothy P Schafer, Beth Stevens, Mariko L Bennett, Frederick C Bennett.

The nervous system comprises a remarkably diverse and complex network of cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS, and highlight exciting new discoveries about their contributions to CNS development, maintenance, and plasticity.

DOI: https://doi.org/10.1101/cshperspect.a041810
Pathol Res Pract. 2024 Sep 25. pii: S0344-0338(24)00525-9. [Epub ahead of print]263 155614

Therapeutic approaches to microglial dysfunction in Alzheimer's disease: Enhancing phagocytosis and metabolic regulation.

Waleed Hassan Almalki, Salem Salman Almujri.

  Microglia are essential in neurogenesis, synaptic pruning, and homeostasis. Nevertheless, aging, and cellular senescence may modify their role, causing them to shift from being shields to being players of neurodegeneration. In the aging brain, the population of microglia increases, followed by enhanced activity of genes related to neuroinflammation. This change increases their ability to cause inflammation, resulting in a long-lasting state of inflammation in the brain that harms the condition of neurons. In Alzheimer's Disease (AD), microglia are located inside amyloid plaques and exhibit an inflammatory phenotype characterized by a diminished ability to engulf and remove waste material, worsening the illness's advancement. Genetic polymorphisms in TREM2, APOE, and CD33 highlight the significant impact of microglial dysfunction in AD. This review examines therapeutic approaches that aim to address microglial dysfunction, such as enhancing the microglial capability to engulf and remove amyloid-β clumps and regulating microglial metabolism and mitochondrial activity. Microglial transplanting and reprogramming advancements show the potential to restore their ability to reduce inflammation. Although there has been notable advancement, there are still voids in our knowledge of microglial biology, including their relationships with other brain cells. Further studies should prioritize the improvement of human AD models, establish standardized methods for characterizing microglia, and explore how various factors influence microglial responses. It is essential to tackle these problems to create effective treatment plans that focus on reducing inflammation in the brain and protecting against damage in age-related neurodegenerative illnesses.

Keywords:  Aging; Alzheimer's; Brain; Microglia; Neurodegeneration

DOI:  https://doi.org/10.1016/j.prp.2024.155614