bims-microg 2024-11-10 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024‒11‒10
twenty-six papers selected by
Marcus Karlstetter, Universität zu Köln

Spatiotemporal transcriptomic map of glial cell response in a mouse model of acute brain ischemia.
Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model.
Noncanonical microglial IL-1β maturation in chronic kidney disease.
Senolytic treatment diminishes microglia and decreases severity of experimental autoimmune encephalomyelitis.
Modulation of Mitochondrial Dynamics by the Angiotensin System in Dopaminergic Neurons and Microglia.
Extracellular vesicles from microglial cells activated by abnormal heparan sulfate oligosaccharides from Sanfilippo patients impair neuronal dendritic arborization.
Gut commensal Agathobacter rectalis alleviates microglia-mediated neuroinflammation against pathogenesis of Alzheimer disease.
Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner.
Minocycline inhibits microglial activation in the CA1 hippocampal region and prevents long-term cognitive sequel after experimental cerebral malaria.
The activation of inflammatory responses in the brain is potentiated by over-expressing acetylcholinesterase in myeloid lineage of transgenic mice.
Compound 7 regulates microglia polarization and attenuates radiation-induced myelopathy via the Nrf2 signaling pathway in vivo and in vitro studies.
Interleukin-6 deficiency reduces neuroinflammation by inhibiting the STAT3-cGAS-STING pathway in Alzheimer's disease mice.
TREM2 signaling in Parkinson's disease: Regulation of microglial function and α-synuclein pathology.
Primary cortical cell tri-culture to study effects of amyloid-β on microglia function and neuroinflammatory response.
Microglia phagocytosis of PNNs mediates PV-positive interneuron dysfunction and associated gamma oscillations in neuroinflammation-induced cognitive impairment in mice.
Luteolin ameliorates chronic stress-induced depressive-like behaviors in mice by promoting the Arginase-1+ microglial phenotype via a PPARγ-dependent mechanism.
Shifts in the spatiotemporal profile of inflammatory phenotypes of innate immune cells in the rat brain following acute intoxication with the organophosphate diisopropylfluorophosphate.
A microglia-containing cerebral organoid model to study early life immune challenges.
A bottom-up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors.
Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer's disease.
Kaempferol improves depression-like behaviors through shifting microglia polarization and suppressing NLRP3 via tilting the balance of PPARγ and STAT1 signaling.
Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice.
Implicative role of Cytokines in Neuroinflammation mediated AD and associated signaling pathways: Current Progress in molecular signaling and therapeutics.
LPS-induced delirium-like behavior and microglial activation in mice correlate with bispectral electroencephalography (BSEEG).
Isoliquiritigenin alleviates neuropathic pain by reducing microglia inflammation through inhibition of the ERK signaling pathway and decreasing CEBPB transcription expression.
Keep neuroinflammation in mind when addressing Alzheimer's disease: A microglia perspective.

Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2404203121

Spatiotemporal transcriptomic map of glial cell response in a mouse model of acute brain ischemia.

Daniel Zucha, Pavel Abaffy, Denisa Kirdajova, Daniel Jirak, Mikael Kubista, Miroslava Anderova, Lukas Valihrach.

  The role of nonneuronal cells in the resolution of cerebral ischemia remains to be fully understood. To decode key molecular and cellular processes that occur after ischemia, we performed spatial and single-cell transcriptomic profiling of the male mouse brain during the first week of injury. Cortical gene expression was severely disrupted, defined by inflammation and cell death in the lesion core, and glial scar formation orchestrated by multiple cell types on the periphery. The glial scar was identified as a zone with intense cell-cell communication, with prominent ApoE-Trem2 signaling pathway modulating microglial activation. For each of the three major glial populations, an inflammatory-responsive state, resembling the reactive states observed in neurodegenerative contexts, was observed. The recovered spectrum of ischemia-induced oligodendrocyte states supports the emerging hypothesis that oligodendrocytes actively respond to and modulate the neuroinflammatory stimulus. The findings are further supported by analysis of other spatial transcriptomic datasets from different mouse models of ischemic brain injury. Collectively, we present a landmark transcriptomic dataset accompanied by interactive visualization that provides a comprehensive view of spatiotemporal organization of processes in the postischemic mouse brain.

Keywords:  glia; ischemic stroke; neuroinflammation; single-cell transcriptomics; spatial transcriptomics

DOI:  https://doi.org/10.1073/pnas.2404203121
Cell Stem Cell. 2024 Oct 30. pii: S1934-5909(24)00367-9. [Epub ahead of print]

Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model.

Antara Rao, Nuo Chen, Min Joo Kim, Jessica Blumenfeld, Oscar Yip, Zherui Liang, David Shostak, Yanxia Hao, Maxine R Nelson, Nicole Koutsodendris, Brian Grone, Leo Ding, Seo Yeon Yoon, Patrick Arriola, Misha Zilberter, Yadong Huang.

  Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory microglial subtypes with elevated MHC-II gene expression enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.

Keywords:  APOE4; Alzheimer’s disease; RNA-seq; amyloid; chimeric disease model; iPSC; microglia; tau; transplantation

DOI:  https://doi.org/10.1016/j.stem.2024.10.005
Nephrol Dial Transplant. 2024 Nov 04. pii: gfae239. [Epub ahead of print]

Noncanonical microglial IL-1β maturation in chronic kidney disease.

Silke Zimmermann, Akash Mathew, Olga Bondareva, Ahmed Elwakiel, Shihai Jiang, Rajiv Rana, Ingo Bechmann, Jürgen Goldschmidt, Nora Klöting, Bilal N Sheikh, Berend Isermann.

  BACKGROUND AND HYPOTHESIS: Organ transplantation reverses cognitive impairment in chronic kidney disease (CKD), indicating that cognitive impairment driven by CKD is therapeutically amendable. We recently demonstrated that impaired cognition in CKD is linked to IL-1β-release from microglia and IL-1R1-signaling in neuronal cells, thereby identifying a signaling pathway that can be exploited therapeutically. However, the mechanism of IL-1β-maturation in microglia in CKD remains unknown. We hypothesized that microglia cells require caspase-1 for CKD-driven cognitive impairment.METHODS: We used a combination of single cell analyses, in situ analyses, genetically modified mouse models (including newly generated Cre-LoxP mouse models) and in vitro models. The current study builds on a recently identified intercellular crosstalk between microglia and neurons that impairs cognition in chronic kidney disease (CKD).
RESULTS: Here, we show that despite NLRP3 inflammasome activation in the brain and protection of mice with constitutive NLRP3 deficiency from CKD-induced cognitive impairment, (i) caspase-1 is not required for IL-1β maturation in microglia and (ii) targeted caspase-1 deficiency in microglia does not improve cognition in CKD mice. These data indicate that IL-1β maturation in microglia is independent of the NLRP3-caspase-1 interaction in CKD. Indeed, microglia activation in CKD induces noncanonical, cathepsin C-caspase-8 mediated IL-1β maturation. Depletion of cathepsin C or caspase-8 blocks IL-1β maturation in microglia. Preliminary analyses suggest that noncanonical microglia IL-1β maturation occurs also in diabetes mellitus.
CONCLUSION: These results identify a noncanonical IL-1β-maturation pathway as a potential therapeutic target to combat microglia-induced neuronal dysfunction in CKD and possible other peripheral diseases.

Keywords:  caspase-8; cathepsins; chronic diseases; cognition; inflammation; microglia signaling

DOI:  https://doi.org/10.1093/ndt/gfae239
J Neuroinflammation. 2024 Nov 01. 21(1): 283

Senolytic treatment diminishes microglia and decreases severity of experimental autoimmune encephalomyelitis.

Sienna S Drake, Aliyah Zaman, Christine Gianfelice, Elizabeth M-L Hua, Kali Heale, Elia Afanasiev, Wendy Klement, Jo Anne Stratton, Alexandre Prat, Stephanie Zandee, Alyson E Fournier.

  BACKGROUND: The role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Much research has shown previously that inflammation can promote cellular senescence. Microglia are a central nervous system innate immune cell that undergo senescence with aging and during neurodegeneration. The contribution of senescent microglia to multiple sclerosis, an inflammatory neurodegenerative disease, is not clear, but microglia are strongly implicated in chronic active lesion pathology, tissue injury, and disease progression. Drugs that could specifically eliminate dysregulated microglia in multiple sclerosis are therefore of great interest to the field.RESULTS: A single-cell analysis of brain tissue from mice subjected to experimental autoimmune encephalomyelitis (EAE), a mouse model of CNS inflammation that models aspects of multiple sclerosis (MS), identified microglia with a strong transcriptional signature of senescence including the presence of BCL2-family gene transcripts. Microglia expressing Bcl2l1 had higher expression of pro-inflammatory and senescence associated genes than their Bcl2l1 negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune genes suggesting they may be proinflammatory and contribute to disease processes in chronic active lesions. Employing a small molecule BCL2-family inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia and macrophages in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice: decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation.
CONCLUSION: These results support the hypothesis that microglia and macrophages exhibit transcriptional features of cellular senescence in EAE and MS, and that microglia expressing Bcl2l1 demonstrate a proinflammatory signature that may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease. Depleting microglia and macrophages using a senolytic results in robust improvement in EAE disease severity, including across measures of neurodegeneration, inflammation, and demyelination, and may therefore represent a novel strategy to address disease progression in multiple sclerosis.

Keywords:  Experimental autoimmune encephalomyelitis; Microglia; Multiple sclerosis; Neuroinflammation; Senescence; Senolytics; Senotherapeutic

DOI:  https://doi.org/10.1186/s12974-024-03278-2
Aging Dis. 2024 Oct 31.

Modulation of Mitochondrial Dynamics by the Angiotensin System in Dopaminergic Neurons and Microglia.

Aloia Quijano, Ana I Rodriguez-Perez, María Alicia Costa-Besada, Andrea Lopez-Lopez, María J Guerra, Jose Luis Labandeira-Garcia, Rita Valenzuela.

Renin-angiotensin system (RAS) dysfunctions have been associated to life-spam, and aging-related diseases, including neurodegenerative diseases, such as Parkinson's disease, and the neuroinflammatory associated processes. Mitochondrial dysfunctions play a major role in aging-related diseases, including dopaminergic neurodegeneration and neuroinflammation. However, the mechanisms of RAS/mitochondria interactions remain to be clarified. In the present work, we studied the role of major RAS components in the mitochondrial dynamics in dopaminergic neurons and microglia using in vitro and in vivo models. In dopaminergic neurons, we observed that activation of the RAS pro-oxidative/pro-inflammatory axis (Angiotensin II/Angiotensin type-1 receptor, AT1/NADPH oxidase complex) produces a dysregulation of mitochondrial dynamics towards mitochondrial fission, via Drp1 phosphorylation at Ser616 and translocation to mitochondria. However, activation of the RAS antioxidative/anti-inflammatory axis, using Angiotensin 1-7, counteracts this effect. RAS components also modulated the microglial inflammatory response through mitochondrial dynamic changes. After interferon-γ-induced activation of human microglial cells, we observed increased mitochondrial fission and superoxide production that was inhibited by Angiotensin 1-7 treatment. Angiotensin 1-7 also inhibited mitochondrial metabolic changes induced by pro-inflammatory microglial activation. The role of RAS in mitochondrial dynamic changes was confirmed in vivo using the LPS-induced inflammation model in wild-type, AT1-KO, and AT2-KO mice. The effect of Angiotensin 1-7 is mediated by IL-10, specifically by decreasing the post-transcriptional phosphorylated Drp1 form, and translocation of STAT3 to mitochondria. Angiotensin 1-7, acting on mitochondrial Angiotensin 1-7 receptors (Mas/Mas related receptors), increased the phosphorylated form of STAT3 at Ser727, which is mediated by mitochondrial PKA activation. In conclusion, the present findings show the role of RAS components in modulation of mitochondrial dynamics and mitochondrial function, revealing the associated signaling pathways. The results lead to better understanding of the effects of RAS dysfunction in aging-related diseases, and particularly dopaminergic degeneration and neuroinflammation in Parkinson's disease.

DOI: https://doi.org/10.14336/AD.2024.0981
Mol Med. 2024 Nov 04. 30(1): 197

Extracellular vesicles from microglial cells activated by abnormal heparan sulfate oligosaccharides from Sanfilippo patients impair neuronal dendritic arborization.

Chloé Dias, Nissrine Ballout, Guillaume Morla, Katia Alileche, Christophe Santiago, Ida Chiara Guerrera, Adeline Chaubet, Jerome Ausseil, Stephanie Trudel.

  BACKGROUND: In mucopolysaccharidosis type III (MPS III, also known as Sanfilippo syndrome), a pediatric neurodegenerative disorder, accumulation of abnormal glycosaminoglycans (GAGs) induces severe neuroinflammation by triggering the microglial pro-inflammatory cytokines production via a TLR4-dependent pathway. But the extent of the microglia contribution to the MPS III neuropathology remains unclear. Extracellular vesicles (EVs) mediate intercellular communication and are known to participate in the pathogenesis of adult neurodegenerative diseases. However, characterization of the molecular profiles of EVs released by MPS III microglia and their effects on neuronal functions have not been described.METHODS: Here, we isolated EVs secreted by the microglial cells after treatment with GAGs purified from urines of Sanfilippo patients (sfGAGs-EVs) or from age-matched healthy subjects (nGAGs-EVs) to explore the EVs' proteins and small RNA profiles using LC-MS/MS and RNA sequencing. We next performed a functional assay by immunofluorescence following nGAGs- or sfGAGs-EVs uptake by WT primary cortical neurons and analyzed their extensions metrics after staining of βIII-tubulin and MAP2 by confocal microscopy.
RESULTS: Functional enrichment analysis for both proteomics and RNA sequencing data from sfGAGs-EVs revealed a specific content involved in neuroinflammation and neurodevelopment pathways. Treatment of cortical neurons with sfGAGs-EVs induced a disease-associated phenotype demonstrated by a lower total neurite surface area, an impaired somatodendritic compartment, and a higher number of immature dendritic spines.
CONCLUSIONS: This study shows, for the first time, that GAGs from patients with Sanfilippo syndrome can induce microglial secretion of EVs that deliver a specific molecular message to recipient naive neurons, while promoting the neuroinflammation, and depriving neurons of neurodevelopmental factors. This work provides a framework for further studies of biomarkers to evaluate efficiency of emerging therapies.

Keywords:  Extracellular vesicle; Heparan sulfate; Microglia; Mucopolysaccharidosis; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1186/s10020-024-00953-1
iScience. 2024 Nov 15. 27(11): 111116

Gut commensal Agathobacter rectalis alleviates microglia-mediated neuroinflammation against pathogenesis of Alzheimer disease.

Xinhuang Lv, Lu Zhan, Tao Ye, Huijia Xie, Zhibo Chen, Yan Lin, Xianlei Cai, Wenwen Yang, Xiaolan Liao, Jiaming Liu, Jing Sun.

  Gut microbiota plays a crucial role in the pathogenesis of Alzheimer disease (AD). Here, we found that AD patients had significantly lower abundance of Agathobacter, which were negatively correlated with cognitive impairment. Animal experiments showed that Agathobacter rectalis (A. rectalis) supplementation increased beneficial commensal bacteria, significantly improved pathological damage, and suppressed microglial activation in APP/PS1 mice. We further demonstrated that butyric acid, a metabolite of A. rectalis, reduced microglial activation and pro-inflammatory factor production via Akt/ nuclear factor κB (NF-κB) signal pathway in vitro. Meanwhile, we revealed that A. rectalis effectively inhibited activation of microglia in the APP/PS1 mice by regulating Akt/ NF-κB pathway. This finding highlights the role of A. rectalis and its metabolite butyrate in mitigating neuroinflammation in AD by modulating the Akt/NF-κB pathway.

Keywords:  Immunology; Microbiome; Neuroscience; Pathophysiology

DOI:  https://doi.org/10.1016/j.isci.2024.111116
J Neuroinflammation. 2024 Nov 01. 21(1): 280

Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner.

Hannah A Staley, Janna E Jernigan, MacKenzie L Bolen, Ann M Titus, Noelle Neighbarger, Cassandra Cole, Kelly B Menees, Rebecca L Wallings, Malú Gámez Tansey.

  Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer's disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying the P522R mutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, the P522R mutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies.

Keywords:  Alzheimer’s disease; Macrophage; PLCG2; Sex differences

DOI:  https://doi.org/10.1186/s12974-024-03271-9
J Neuroimmunol. 2024 Oct 29. pii: S0165-5728(24)00199-1. [Epub ahead of print]397 578480

Minocycline inhibits microglial activation in the CA1 hippocampal region and prevents long-term cognitive sequel after experimental cerebral malaria.

E T Moreira, M P Lourenço, T Cunha-Fernandes, T I Silva, L D Siqueira, H C Castro-Faria-Neto, P A Reis.

  Cerebral malaria is the worst complication of malaria infection, has a high mortality rate, and may cause different neurodysfunctions, including cognitive decline. Neuroinflammation is an important cause of cognitive damage in neurodegenerative diseases, and microglial cells can be activated in a disease-associated profile leading to tissue damage and neuronal death. Here, we demonstrated that treatment with minocycline reduced blood-brain barrier breakdown and modulated ICAM1 mRNA expression; reduced proinflammatory cytokines, such as TNF-α, IL-1β, IFN-γ, and IL-6; and prevented long-term cognitive decline in contextual and aversive memory tasks. Taken together, our data suggest that microglial cells are activated during experimental cerebral malaria, leading to neuroinflammatory events that end up in cognitive damage. In addition, pharmacological modulation of microglial activation, by drugs such as minocycline may be an important therapeutic strategy in the prevention of long-term memory impairment.

Keywords:  Cerebral malaria; Cognitive impairment; Microglial activation; Microglial cells; minocycline; neuroinflammation

DOI:  https://doi.org/10.1016/j.jneuroim.2024.578480
J Neurochem. 2024 Nov 05.

The activation of inflammatory responses in the brain is potentiated by over-expressing acetylcholinesterase in myeloid lineage of transgenic mice.

Yingjie Xia, Xiaoyang Wang, Maggie Suisui Guo, Jiahui Wu, Jin Gao, Tina T X Dong, Karl W K Tsim.

  Acetylcholinesterase (AChE) has functions in neuroinflammation, beyond its classical role in neurotransmission. Understanding the role of AChE in neuroinflammation is of great significance, as it highlights the potential therapeutic targets for the treatment of neurodegenerative diseases. In an in vitro study, the expression of AChE was up-regulated in lipopolysaccharide (LPS)-induced microglia/macrophage and contrarily potentiated the inflammatory responses via disturbing the cholinergic anti-inflammatory pathway (CAP). However, the regulation of AChE in neuroinflammation has not been revealed in vivo yet. Here, we aim to uncover the inflammatory roles of microglial AChE in LPS-induced neuroinflammation by using the conditional AChE over-expression mouse model. AChE was specifically over-expressed in the myeloid cell linkage of mouse by applying CRISPR/cas9 combined with Cre-LoxP system. LPS was intraperitoneally injected into the mice to induce inflammation. The results showed that the inflammation, induced by LPS, was aggravated in the brain of transgenic mice having over-expression of AChE in microglia. The expressions of pro-inflammatory cytokines were robustly up-regulated in the brains of LPS-treated transgenic mice, as compared to the LPS-treated wildtypes. In parallel, the activations of microglia and astrocytes in hippocampus were enhanced significantly in AChE transgenic mice. Transcriptomics analysis further confirmed the severer inflammation in the transgenic mice than the wildtype after LPS administration. These findings shed light on the regulation of microglial AChE in neuroinflammation in vivo for the first time, presenting another angle to understand the role of AChE in neurodegenerative diseases.

Keywords:  RNA‐seq; acetylcholinesterase; microglia; neuroinflammation

DOI:  https://doi.org/10.1111/jnc.16251
Mol Med. 2024 Nov 04. 30(1): 198

Compound 7 regulates microglia polarization and attenuates radiation-induced myelopathy via the Nrf2 signaling pathway in vivo and in vitro studies.

Han Wu, Jianping Wu, Jianzhuo Jiang, Zeyu Qian, Shuang Yang, Yanze Sun, Hongxia Cui, Shengwen Li, Peng Zhang, Zhiqiang Zhou.

  BACKGROUND: Radiation-induced myelopathy (RM) is a significant complication of radiotherapy with its mechanisms still not fully understood and lacking effective treatments. Compound 7 (C7) is a newly identified, potent, and selective inhibitor of the Keap1-Nrf2 interaction. This study aimed to explore the protective effects and mechanisms of C7 on RM in vitro and in vivo.METHODS: Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), reactive oxygen species (ROS) and mitochondrial polarization, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, genetic editing techniques, locomotor functions, and tissue staining were employed to explore the protective effects and underlying mechanisms of C7 in radiation-induced primary rat microglia and BV2 cells, as well as RM rat models.
RESULTS: In this study, we found that C7 inhibited the production of pro-inflammation cytokines and oxidative stress induced by irradiation in vitro. Further, the data revealed that radiation worsened the locomotor functions in rats, and C7 significantly improved histological and functional recovery in RM rats. Mechanically, C7 activated Nrf2 signaling and promoted the microglia transformation from M1 to M2 phenotype.
CONCLUSION: C7 could ameliorate RM by boosting Nrf2 signaling and promoting M2 phenotype microglia polarization in vitro and in vivo.

Keywords:  Compound 7; Microglia; Nrf2; Polarization; Radiation-induced myelopathy

DOI:  https://doi.org/10.1186/s10020-024-00951-3
J Neuroinflammation. 2024 Nov 01. 21(1): 282

Interleukin-6 deficiency reduces neuroinflammation by inhibiting the STAT3-cGAS-STING pathway in Alzheimer's disease mice.

Min Liu, Jirong Pan, Xiaomeng Li, Xueling Zhang, Fan Tian, Mingfeng Li, Xinghan Wu, Ling Zhang, Chuan Qin.

  BACKGROUND: The Interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway, along with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, are critical contributors to neuroinflammation in Alzheimer's disease (AD). Although previous research outside the context of AD has indicated that the IL-6-STAT3 pathway may regulate the cGAS-STING pathway, the exact molecular mechanisms through which IL-6-STAT3 influences cGAS-STING in AD are still not well understood.METHODS: The activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of 5×FAD and WT mice was analyzed using WB and qRT-PCR. To explore the effects of IL-6 deficiency, Il6+/- mice were crossed with 5×FAD mice, and the subsequent impact on hippocampal STAT3 pathway activity, cGAS-STING pathway activation, amyloid pathology, neuroinflammation, and cognitive function was evaluated through WB, qRT-PCR, immunohistochemistry, ThS staining, ELISA, and behavioral tests. The regulatory role of STAT3 in the transcription of the Cgas and Sting genes was further validated using ChIP-seq and ChIP-qPCR on hippocampal tissue from 5×FAD and Il6-/-: 5×FAD mice. Additionally, in the BV2 microglial cell line, the impact of STAT3 activation on the transcriptional regulation of Cgas and Sting genes, as well as the production of inflammatory mediators, was examined through WB and qRT-PCR.
RESULTS: We observed marked activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of AD mice, which was attenuated in the absence of IL-6. IL-6 deficiency reduced beta-amyloid deposition and neuroinflammation in the hippocampus of AD mice, contributing to cognitive improvements. Further analysis revealed that STAT3 directly regulates the transcription of both the Cgas and Sting genes. These findings suggest a potential mechanism involving the STAT3-cGAS-STING pathway, wherein IL-6 deficiency mitigates neuroinflammation in AD mice by modulating this pathway.
CONCLUSION: These findings indicate that the STAT3-cGAS-STING pathway is critical in mediating neuroinflammation associated with AD and may represent a potential therapeutic target for modulating this inflammatory process in AD.

Keywords:  Alzheimer’s disease; IL-6; Neuroinflammation; STAT3; STING; cGAS

DOI:  https://doi.org/10.1186/s12974-024-03277-3
Int Immunopharmacol. 2024 Oct 26. pii: S1567-5769(24)01968-4. [Epub ahead of print]143(Pt 2): 113446

TREM2 signaling in Parkinson's disease: Regulation of microglial function and α-synuclein pathology.

Sijia Yin, Xiaosa Chi, Fang Wan, Yunna Li, Qiulu Zhou, Liang Kou, Yadi Sun, Jiawei Wu, Wenkai Zou, Yiming Wang, Zongjie Jin, Jinsha Huang, Nian Xiong, Yun Xia, Tao Wang.

  BACKGROUND: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, abnormal accumulation of α-synuclein (α-syn), and microglial activation. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates multiple functions of microglia in the brain, and several studies have shown that TREM2 variant R47H is a risk factor for PD. However, the regulation of microglia by TREM2 in PD remains poorly understood.METHODS: We constructed PD cell and animal models using α-syn preformed fibrils. siRNA knockdown and lentiviral overexpression were used to perturb TREM2 levels in cells, and TREM2 knockout mice and lentiviral overexpression was used in animal models to investigate the effects of TREM2 on microglial function, α-syn-related pathology, and dopaminergic neuron degeneration.
RESULTS: Microglia phagocytosed α-syn preformed fibrils in a concentration- and time-dependent manner, with some capacity to degrade α-syn aggregates. TREM2 expression increased in PD. In the context of PD, TREM2 knockout mice exhibited worsened pathological α-syn spread, decreased microglial reactivity, and increased loss of TH-positive neurons in the substantia nigra compared to wild-type mice. TREM2 overexpression enhanced reactive microglial aggregation towards the pathological site. Cellular experiments revealed that reduced TREM2 impaired microglial phagocytosis and proliferation, but enhanced autophagy via the PI3K/AKT/mTOR pathway.
CONCLUSION: TREM2 signaling in PD maintains microglial phagocytosis, proliferation, and reactivity, stabilizing autophagy and proliferation via the PI3K/AKT/mTOR pathway. Regulating TREM2 levels may be beneficial in PD treatment.

Keywords:  Alpha-synuclein; Microglia; PI3K-AKT-mTOR pathway; Parkinson’s disease; TREM2

DOI:  https://doi.org/10.1016/j.intimp.2024.113446
J Alzheimers Dis. 2024 Nov 05. 13872877241291142

Primary cortical cell tri-culture to study effects of amyloid-β on microglia function and neuroinflammatory response.

Hyehyun Kim, Bryan Le, Noah Goshi, Kan Zhu, Ana Cristina Grodzki, Pamela J Lein, Min Zhao, Erkin Seker.

  BACKGROUND: Microglia play a critical role in neurodegenerative disorders, such as Alzheimer's disease, where alterations in microglial function may result in pathogenic amyloid-β (Aβ) accumulation, chronic neuroinflammation, and deleterious effects on neuronal function. However, studying these complex factors in vivo, where numerous confounding processes exist, is challenging, and until recently, in vitro models have not allowed sustained culture of critical cell types in the same culture.OBJECTIVE: We employed a rat primary tri-culture (neurons, astrocytes, and microglia) model and compared it to co-culture (neurons and astrocytes) and mono-culture (microglia) to study microglial function (i.e., motility and Aβ clearance) and proteomic response to exogenous Aβ.
METHODS: The cultures were exposed to fluorescently-labeled Aβ (FITC-Aβ) particles for varying durations. Epifluorescence microscopy images were analyzed to quantify the number of FITC-Aβ particles and assess cytomorphological features. Cytokine profiles from conditioned media were obtained. Live-cell imaging was employed to extract microglia motility parameters.
RESULTS: FITC-Aβ particles were more effectively cleared in the tri-culture compared to the co-culture. This was attributed to microglia engulfing FITC-Aβ particles, as confirmed via epifluorescence and confocal microscopy. FITC-Aβ treatment significantly increased microglia size, but had no significant effect on neuronal surface coverage or astrocyte size. Upon FITC-Aβ treatment, there was a significant increase in proinflammatory cytokines in tri-culture, but not in co-culture. Aβ treatment altered microglia motility evident as a swarming-like motion.
CONCLUSIONS: The results suggest that neuron-astrocyte-microglia interactions influence microglia function and highlight the utility of the tri-culture model for studies of neuroinflammation, neurodegeneration, and cell-cell communication.

Keywords:  Alzheimer's disease; amyloid-beta; cell motility; cytokine profile; live cell imaging; microglia; neural cell culture; neuroinflammation; phagocytosis

DOI:  https://doi.org/10.1177/13872877241291142
Neuropharmacology. 2024 Nov 02. pii: S0028-3908(24)00374-5. [Epub ahead of print]262 110205

Microglia phagocytosis of PNNs mediates PV-positive interneuron dysfunction and associated gamma oscillations in neuroinflammation-induced cognitive impairment in mice.

Kai Liu, Yu-Zhu Gao, Xin-Miao Wu, Xiao-Yi Hu, Cui-Na Shi, Qiu-Li He, Hai-Peng Wu, Hao Yao, Da-Qing Ma, Jian-Jun Yang, Mu-Huo Ji.

  Neuroinflammation, characterized by activation of glial cells, plays a critical role in central nervous system disorders. However, the precise mechanisms of neuroinflammation contributing to cognitive impairment remain elusive. Perineuronal nets (PNNs) are extracellular matrixes that envelop the cell bodies and dendrites of parvalbumin (PV)-positive interneurons and may be mediated by apolipoprotein E (ApoE) gene. To investigate whether disruption of PNNs associated with ApoE is implicated in neuroinflammation-induced cognitive impairment, we established a neuroinflammation model by administering lipopolysaccharides (LPS) at 0.5 mg/kg for 7 consecutive days. Cognitive function was assessed using the open field, Y-maze, and novel object recognition tests, and neural oscillations were also recorded. Furthermore, differentially expressed genes in microglia within the hippocampus were identified through single-cell RNA sequencing analysis. Overexpression of hyaluronan and proteoglycan link protein 1 (Hapln1) and ApoE knockdown were carried out through adeno-associated virus (AAV) injection to C57BL/6J mice and CX3CR1-CreERT2 mice, respectively. It was found that LPS-induced neuroinflammation impaired cognitive function by reducing PNNs and PV-positive interneurons' outputs, as well as disrupting gamma (γ) oscillations in the hippocampal CA1. Overexpression of Hapln1 was able to restore PV-positive interneurons and γ oscillations, ultimately alleviating the cognitive impairment. Mechanistically, LPS-triggered microglial activation leads to the phagocytosis of PNNs, a process influenced by ApoE. Notably, prevention of PNNs engulfment through targeting microglial ApoE in the CA1 improved cognitive impairment. Collectively, our study suggested that microglial phagocytosis of PNNs plays a key role in neuroinflammation-induced cognitive impairment, which is probably mediated by the ApoE.

Keywords:  Gamma oscillations; Microglia; Neuroinflammation; PNNs; PV-Positive interneurons

DOI:  https://doi.org/10.1016/j.neuropharm.2024.110205
Acta Pharmacol Sin. 2024 Nov 04.

Luteolin ameliorates chronic stress-induced depressive-like behaviors in mice by promoting the Arginase-1+ microglial phenotype via a PPARγ-dependent mechanism.

Nai-Jun Yuan, Wen-Jun Zhu, Qing-Yu Ma, Min-Yi Huang, Rou-Rou Huo, Kai-Jie She, Jun-Ping Pan, Ji-Gang Wang, Jia-Xu Chen.

  Accumulating evidence shows that neuroinflammation substantially contributes to the pathology of depression, a severe psychiatric disease with an increasing prevalence worldwide. Although modulating microglial phenotypes is recognized as a promising therapeutic strategy, effective treatments are still lacking. Previous studies have shown that luteolin (LUT) has anti-inflammatory effects and confers benefits on chronic stress-induced depression. In this study, we investigated the molecular mechanisms by which LUT regulates the functional phenotypes of microglia in mice with depressive-like behaviors. Mice were exposed to chronic restraint stress (CRS) for 7 weeks, and were administered LUT (10, 30, 40 mg· kg-1 ·day-1, i.g.) in the last 4 weeks. We showed that LUT administration significantly ameliorated depressive-like behaviors and decreased hippocampal inflammation. LUT administration induced pro-inflammatory microglia to undergo anti-inflammatory arginase (Arg)-1+ phenotypic polarization, which was associated with its antidepressant effects. Furthermore, we showed that LUT concentration-dependently increased the expression of PPARγ in LPS + ATP-treated microglia and the hippocampus of CRS-exposed mice, promoting the subsequent inhibition of the NLRP3 inflammasome. Molecular dynamics (MD) simulation and microscale thermophoresis (MST) analysis confirmed a direct interaction between LUT and peroxisome proliferator-activated receptor gamma (PPARγ). By using the PPARγ antagonist GW9662, we demonstrated that LUT-driven protection, both in vivo and in vitro, resulted from targeting PPARγ. First, LUT-induced Arg-1+ microglia were no longer detected when PPARγ was blocked. Next, LUT-mediated inhibition of the NLRP3 inflammasome and downregulation of pro-inflammatory cytokine production were reversed by the inhibition of PPARγ. Finally, the protective effects of LUT, which attenuated the microglial engulfment of synapses and prevented apparent synapse loss in the hippocampus of CRS-exposed mice, were eliminated by blocking PPARγ. In conclusion, this study showed that LUT ameliorates CRS-induced depressive-like behaviors by promoting the Arg-1+ microglial phenotype through a PPARγ-dependent mechanism, thereby alleviating microglial pro-inflammatory responses and reversing microglial phagocytosis-mediated synapse loss.

Keywords:  PPARγ; depression; luteolin; microglia; neuroinflammation; phagocytosis

DOI:  https://doi.org/10.1038/s41401-024-01402-9
J Neuroinflammation. 2024 Nov 04. 21(1): 285

Shifts in the spatiotemporal profile of inflammatory phenotypes of innate immune cells in the rat brain following acute intoxication with the organophosphate diisopropylfluorophosphate.

Peter M Andrew, Jeremy A MacMahon, Pedro N Bernardino, Yi-Hua Tsai, Brad A Hobson, Valerie A Porter, Sydney L Huddleston, Audrey S Luo, Donald A Bruun, Naomi H Saito, Danielle J Harvey, Amy Brooks-Kayal, Abhijit J Chaudhari, Pamela J Lein.

  Acute intoxication with cholinesterase inhibiting organophosphates (OP) can produce life-threatening cholinergic crisis and status epilepticus (SE). Survivors often develop long-term neurological consequences, including spontaneous recurrent seizures (SRS) and impaired cognition. Numerous studies implicate OP-induced neuroinflammation as a pathogenic mechanism contributing to these chronic sequelae; however, little is known about the inflammatory phenotype of innate immune cells in the brain following acute OP intoxication. Thus, the aim of this study was to characterize the natural history of microglial and astrocytic inflammatory phenotypes following acute intoxication with the OP, diisopropylfluorophosphate (DFP). Adult male and female Sprague-Dawley rats were administered a single dose of DFP (4 mg/kg, sc) followed by standard medical countermeasures. Within minutes, animals developed benzodiazepine-resistant SE as determined by monitoring seizures using a modified Racine scale. At 1, 3, 7, 14, and 28 d post-exposure (DPE), neuroinflammation was assessed using translocator protein (TSPO) positron emission tomography (PET) and magnetic resonance imaging (MRI). In both sexes, we observed consistently elevated radiotracer uptake across all examined brain regions and time points. A separate group of animals was euthanized at these same time points to collect tissues for immunohistochemical analyses. Colocalization of IBA-1, a marker for microglia, with iNOS or Arg1 was used to identify pro- and anti-inflammatory microglia, respectively; colocalization of GFAP, a marker for astrocytes, with C3 or S100A10, pro- and anti-inflammatory astrocytes, respectively. We observed shifts in the inflammatory profiles of microglia and astrocyte populations during the first month post-intoxication, largely in hyperintense inflammatory lesions in the piriform cortex and amygdala regions. In these areas, iNOS+ proinflammatory microglial cell density peaked at 3 and 7 DPE, while anti-inflammatory Arg1+ microglia cell density peaked at 14 DPE. Pro- and anti-inflammatory astrocytes emerged within 7 DPE, and roughly equal ratios of C3+ pro-inflammatory and S100A10+ anti-inflammatory astrocytes persisted at 28 DPE. In summary, microglia and astrocytes adopted mixed inflammatory phenotypes post-OP intoxication, which evolved over one month post exposure. These activated cell populations were most prominent in the piriform and amygdala areas and were more abundant in males compared to females. The temporal relationship between microglial and astrocytic responses suggests that initial microglial activity may influence delayed, persistent astrocytic responses. Further, our findings identify putative windows for inhibition of OP-induced neuroinflammatory responses in both sexes to evaluate the therapeutic benefit of anti-inflammation in this context.

Keywords:  Astrocytes; Microglia; Nerve agent; Pesticide; Seizures; Status epilepticus

DOI:  https://doi.org/10.1186/s12974-024-03272-8
Brain Behav Immun. 2024 Nov 03. pii: S0889-1591(24)00688-3. [Epub ahead of print]

A microglia-containing cerebral organoid model to study early life immune challenges.

Alice Buonfiglioli, Raphael Kübler, Roy Missall, Renske De Jong, Stephanie Chan, Verena Haage, Stefan Wendt, Ada J Lin, Daniele Mattei, Mara Graziani, Brooke Latour, Frederieke Gigase, Rebecca Chiu, Ya Zhang, Haakon B Nygaard, Philip L De Jager, Lot D De Witte.

  Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

Keywords:  Cerebral organoid; IFN-γ; Immune challenge; Microglia; Neurodevelopmental disorders

DOI:  https://doi.org/10.1016/j.bbi.2024.11.008
Glia. 2024 Nov 04.

A bottom-up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors.

Noelia Rodriguez-Iglesias, Iñaki Paris, Jorge Valero, Lorena Cañas-Zabala, Alejandro Carretero, Klas Hatje, Jitao David Zhang, Christoph Patsch, Markus Britschgi, Simon Gutbier, Amanda Sierra.

  Phagocytosis is an indispensable function of microglia, the brain professional phagocytes. Microglia is particularly efficient phagocytosing cells that undergo programmed cell death (apoptosis) in physiological conditions. However, mounting evidence suggests microglial phagocytosis dysfunction in multiple brain disorders. These observations prompted us to search for phagocytosis modulators (enhancers or inhibitors) with therapeutic potential. We used a bottom-up strategy that consisted on the identification of phagocytosis modulators using phenotypic high throughput screenings (HTSs) in cell culture and validation in organotypic cultures and in vivo. We performed two complementary HTS campagnes: at Achucarro, we used primary cultures of mouse microglia and compounds of the Prestwick Chemical Library; at Roche, we used human iPSC derived macrophage-like cells and a proprietary chemo-genomic library with 2200 compounds with known mechanism-of-action. Next, we validated the more robust compounds using hippocampal organotypic cultures and identified two phagocytosis inhibitors: trifluoperazine, a dopaminergic and adrenergic antagonist used as an antipsychotic and antineoplastic; and deoxytubercidin, a ribose derivative. Finally, we tested whether these compounds were able to modulate phagocytosis of apoptotic newborn cells in the adult hippocampal neurogenic niche in vivo by administering them into the mouse hippocampus using osmotic minipumps. We confirmed that both trifluoperazine and deoxytubercidin have anti-phagocytic activity in vivo, and validated our bottom-up strategy to identify novel phagocytosis modulators. These results show that chemical libraries with annotated mechanism of action are an starting point for the pharmacological modulation of microglia in drug discovery projects aiming at the therapeutic manipulation of phagocytosis in brain diseases.

Keywords:  apoptosis; deoxytubercidin; hts; microglia; phagocytosis; screening; trifluoperazine

DOI:  https://doi.org/10.1002/glia.24637
J Extracell Vesicles. 2024 Nov;13(11): e12519

Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer's disease.

Leelavathi N Madhu, Maheedhar Kodali, Raghavendra Upadhya, Shama Rao, Yogish Somayaji, Sahithi Attaluri, Bing Shuai, Maha Kirmani, Shreyan Gupta, Nathaniel Maness, Xiaolan Rao, James J Cai, Ashok K Shetty.

  As current treatments for Alzheimer's disease (AD) lack disease-modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti-inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC-NSC-EVs in 3-month-old 5xFAD mice. IN administered hiPSC-NSC-EVs incorporated into microglia, including plaque-associated microglia, and encountered astrocyte soma and processes in the brain. Single-cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease-associated microglia, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-inflammasome and interferon-1 (IFN-1) signalling displayed reduced expression in microglia. Adding hiPSC-NSC-EVs to cultured human microglia challenged with amyloid-beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN-1 and interleukin-6 signalling. Furthermore, the modulatory effects of hiPSC-NSC-EVs on microglia in the hippocampus persisted 2 months post-EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen-activated protein kinase and IFN-1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid-beta plaques, and p-tau were also reduced in the hippocampus. Such modulatory effects of hiPSC-NSC-EVs also led to better cognitive and mood function. Thus, early hiPSC-NSC-EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid-beta plaque load, and p-tau. These results reflect the first demonstration of the efficacy of hiPSC-NSC-EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.

Keywords:  Anti‐inflammatory effects; disease‐associated microglia; extracellular vesicles; human induced pluripotent stem cell‐derived neural stem cells; inflammasomes; interferon 1 signalling; mitogen‐activated protein kinase signalling

DOI:  https://doi.org/10.1002/jev2.12519
Int Immunopharmacol. 2024 Nov 03. pii: S1567-5769(24)02060-5. [Epub ahead of print]143(Pt 3): 113538

Kaempferol improves depression-like behaviors through shifting microglia polarization and suppressing NLRP3 via tilting the balance of PPARγ and STAT1 signaling.

Pan Su, Liming Liu, Yuhang Gong, Shuaijun Peng, Xiangli Yan, Ming Bai, Erping Xu, Yucheng Li.

  BACKGROUND: The pathogenesis of depression is largely influenced by dyshomeostasis of neuroinflammation regulated by microglia M1/M2 polarization, and NLRP3 inflammasome acts critical roles in shifting microglia polarization. Kaempferol (Kae), a major flavonoid in edible plants, possesses anti-inflammation and anti-depression capacity, but its underlying cellular and molecular mechanisms of antidepressive effect have not yet fully explored.METHODS: In vivo studies with lipopolysaccharide (LPS)-induced depressive mice were carried out to evaluate antidepressant effect of Kae. In vitro, BV2 microglia cell line stimulated by LPS along with IFN-γ to detect pharmacological effects of Kae on microglia polarization and NLRP3. Based on two depression-related GEO datasets (GSE54570 and GSE54568) and the potential targets of Kae obtained from GeneCards database, enrichment analysis and protein-protein interaction (PPI) network construction reveal potential therapeutic targets of Kae for depression. Then the precise antidepressant mechanisms of Kae were verified by western blot and immunofluorescent staining in vivo and vitro.
RESULTS: Our results showed that Kae significantly improves LPS-induced depressive behaviors and alleviates neuroinflammation in prefrontal cortex. Moreover, Kae obviously shifted microglia polarization to M2 phenotype, and also suppressed NLRP3 in prefrontal cortex and BV2. Enrichment analysis and PPI network construction suggested PPARγ and STAT1 signaling are related to regulation of NLRP3 in depression. Furtherly, Kae remarkably enhanced PPARγ activation and inhibited nuclear translocation of p-STAT1 in microglia of prefrontal cortex and BV2. Importantly, pre-incubation with PPARγ antagonist T0070907 or overexpression with CASTAT1 (constitutively active STAT1) both prevented pharmacologic effects of Kae on shifting microglia polarization and suppressing NLRP3 in BV2. Noteworthily, T0070907 significantly blocked the inhibitory effect of Kae on STAT1 while overexpression with CASTAT1 abolished the effect of Kae on PPARγ activation in BV2. Above results suggested that pharmacologic effects of Kae on microglia polarization and NLRP3 are dependent on the balance of counter-regulatory PPARγ and STAT1 signaling.
CONCLUSION: Our results indicated that the shifting microglia polarization and suppression of NLRP3 via tilting the balance of PPARγ and STAT1 signaling may be the antidepressant mechanism of Kae, which provides a novel perspective for elucidating antidepressive effect of Kae.

Keywords:  Anti-depression; Kaempferol; M1/M2 polarization; NLRP3 inflammasome; PPARγ and STAT1 signaling

DOI:  https://doi.org/10.1016/j.intimp.2024.113538
Neuropharmacology. 2024 Oct 26. pii: S0028-3908(24)00369-1. [Epub ahead of print] 110200

Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice.

Rui Wang, Li Zhu, Yunting Fan, Huiqing Du, Wei Han, Fanglin Guan, Yingjie Zhu, Tong Ni, Teng Chen.

  The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.

Keywords:  D3R; GSK3β; NAc; miR-29c; microglia; reward

DOI:  https://doi.org/10.1016/j.neuropharm.2024.110200
Ageing Res Rev. 2023 Oct 28. pii: S1568-1637(23)00257-X. [Epub ahead of print] 102098

Implicative role of Cytokines in Neuroinflammation mediated AD and associated signaling pathways: Current Progress in molecular signaling and therapeutics.

Sneha Kumari, Rishika Dhapola, Prajjwal Sharma, Sunil K Singh, Dibbanti HariKrishna Reddy.

  Alzheimer's Disease (AD) is one of the most devastating age-related disorder causing significant social and economic burden worldwide. It affects the cognitive and social behavior of individuals and characterized by accumulation of Aβ, phosphorylated tau and cytokines formation. The synthesis and release of cytokines are regulated by specific groups of immune and non-immune cells in response to microglia or astrocyte activation through multiple pathways. Physiologically, microglia assert an anti-inflammatory, quiescent state with minimal cytokine expression and little phagocytic activity in motion to carry out their housekeeping role to eliminate pathogens, aggregated Aβ and tau protein. However, they develop a phagocytic nature and overexpress cytokine gene modules in response to certain stimuli in AD. Microglia and astrocytes upon chronic activation release an enormous amount of inflammatory cytokines due to interaction with formed Aβ and neurofibrillary tangle. Gut microbiota dysbiosis also stimulates the release of inflammatory cytokines contributing to AD pathogenesis. In addition, the dysregulation of few signaling pathways significantly influences the development of disease, and the pace of advancement also rises with age. This review sheds light on multiple pathways results into neuroinflammation triggered by activated cytokines worsening AD pathology and making it an appropriate target for AD treatment. This review also included drugs targeting different neuroinflammation pathways under clinical and preclinical studies that are found to be effective in attenuating the disease pathology.

Keywords:  Astrocytes; Aβ; Cytokines; Drugs; Gut microbiota–brain axis; Interleukin; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1016/j.arr.2023.102098
J Gerontol A Biol Sci Med Sci. 2024 Nov 04. pii: glae261. [Epub ahead of print]

LPS-induced delirium-like behavior and microglial activation in mice correlate with bispectral electroencephalography (BSEEG).

Tsuyoshi Nishiguchi, Kyosuke Yamanishi, Nipun Gorantla, Akiyoshi Shimura, Tomoteru Seki, Takaya Ishii, Bun Aoyama, Johnny R Malicoat, Nathan James Phuong, Nicole Jade Dye, Takehiko Yamanashi, Masaaki Iwata, Gen Shinozaki.

  Delirium is a multifactorial medical condition characterized by impairment across various mental functions and is one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Research focused on delirium has proven to be challenging due to a lack of objective measures for diagnosing patients, and few laboratory models have been validated. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes. We applied BSEEG to validate a lipopolysaccharide (LPS)-induced mouse model of delirium. Moreover, we investigated the relationship between BSEEG score, delirium-like behaviors, and microglia activation in hippocampal dentate gyrus and cortex regions in young and aged mice. There was a significant correlation between BSEEG score and impairment of attention in young mice. Additionally, there was a significant correlation between BSEEG score and microglial activation in hippocampal dentate gyrus and cortex regions in young and aged mice. We have successfully validated the BSEEG method by showing its associations with a level of behavioral change and microglial activation in an LPS-induced mouse model of delirium. In addition, the BSEEG method was able to sensitively capture an LPS-induced delirium-like condition that behavioral tests could not capture because of a hypoactive state.

Keywords:  aging; behavioral test; bispectral electroencephalography (BSEEG); delirium; microglia

DOI:  https://doi.org/10.1093/gerona/glae261
Int Immunopharmacol. 2024 Nov 02. pii: S1567-5769(24)02058-7. [Epub ahead of print]143(Pt 3): 113536

Isoliquiritigenin alleviates neuropathic pain by reducing microglia inflammation through inhibition of the ERK signaling pathway and decreasing CEBPB transcription expression.

Zikun Wang, Shu Jia, Xizhi Kang, Shang Chen, Lu Zhang, ZhiKang Tian, Xiao Liang, Chunyang Meng.

  BACKGROUND: Natural compounds are invaluable for their therapeutic effects in treating various diseases. Isoliquiritigenin (ISL) stands out due to its potent anti-inflammatory and antioxidative properties, offering significant therapeutic effects in many diseases. However, there is currently no existing literature on the role of ISL in neuropathic pain treatment.METHODS: We used lipopolysaccharide to stimulate BV-2 microglia in order to evaluate the inhibitory effects of ISL on neuroinflammation. Proteomics data and protein-protein interaction network analysis were used to identify differential proteins expressed in BV-2 microglia treated with ISL. This allowed for the identification of targets impacted by ISL action. Additionally, we assessed the analgesic efficacy of ISL in a mouse model of chronic constriction injury of the sciatic nerve (CCI) and investigated its inhibitory influence on pro-inflammatory cytokine production and spinal microglia activation.
RESULTS: Our results indicate that ISL efficiently inhibits BV-2 microglia activation and pro-inflammatory cytokine expression. Furthermore, CEBPB has been recognized as a possible target for ISL activity. Crucially, microglia activation was successfully reduced by CEBPB knockdown. Functional recovery tests carried out later on validated that ISL works by specifically inhibiting the ERK/CEBPB signaling pathway. In vivo studies showed that giving mice ISL reduces the mechanical and thermal pain caused on by chronic contraction injuries.
CONCLUSION: The analgesic effect of ISL on neuropathic pain primarily stems from its ability to inhibit the activation of spinal microglia and neuroinflammation. This mechanism may be attributed to the capacity of ISL to suppress microglial activation, reduce the expression of pro-inflammatory cytokines by inhibiting the ERK signaling pathway, and decrease transcriptional expression of CEBPB.

Keywords:  CEBPB; ERK; Isoliquiritigenin; Microglial activation; Neuropathic pain

DOI:  https://doi.org/10.1016/j.intimp.2024.113536
J Alzheimers Dis. 2024 Nov 03. 13872877241290693

Keep neuroinflammation in mind when addressing Alzheimer's disease: A microglia perspective.

Stefania Gessi, Prisco Mirandola, Stefania Merighi.

  This commentary offers a detailed examination of a newly published paper on the effects of small molecule decoys of amyloid-β (Aβ) aggregation on microglial activation. It was discovered that the NSC16224 decoy peptide inhibited proinflammatory cytokines TNFα and IL6 release from microglia in response to Aβ40 and Aβ42 treatment. The research addresses the potential of blocking a sequence of events that lead to the progression of Alzheimer's disease (AD). Here, we discuss the significance of these results in neuroinflammation, highlighting the greater implications for how decoy peptides would be interesting for the research and development of new drugs for AD therapy.

Keywords:  Alzheimer's disease; amyloid-β aggregation; drug; microglia; neuroinflammation

DOI:  https://doi.org/10.1177/13872877241290693