bims-microg 2024-08-18 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–08–18
twenty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism.
The dopamine analogue CA140 alleviates AD pathology, neuroinflammation, and rescues synaptic/cognitive functions by modulating DRD1 signaling or directly binding to Abeta.
C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model.
Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease.
A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.
Characterizing microglial signaling dynamics during inflammation using single-cell mass cytometry.
Mechanism of neurodegeneration mediated by clonal inflammatory microglia.
Human brain organoids containing microglia that have arisen innately adapt to a β-amyloid challenge better than those in which microglia are integrated by co-culture.
Microglial process convergence onto injured axonal swellings, a human postmortem brain tissue study.
Assembling Retinal Organoids with Microglia.
Hyperglycemia-induced Sirt3 downregulation increases microglial aerobic glycolysis and inflammation in diabetic neuropathic pain pathogenesis.
Soluble TGF-β decoy receptor TGFBR3 exacerbates Alzheimer's disease pathology by modifying microglial function.
Role of microglia in diabetic neuropathic pain.
Neuroinflammation in Parkinson's disease: focus on the relationship between miRNAs and microglia.
Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction.
Epigenetic heterogeneity shapes the transcriptional landscape of regional microglia.
Sphingosine-1-phosphate signaling regulates the ability of Müller glia to become neurogenic, proliferating progenitor-like cells.
Androgen deprivation exacerbates AD pathology by promoting the loss of microglia in an age-dependent manner.
Microglial activation and polarization in type 2 diabetes-related cognitive impairment: A focused review of pathogenesis.
Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.
Bulk-RNA and single-nuclei RNA seq analyses reveal the role of lactate metabolism-related genes in Alzheimer's disease.
SIRT2 regulates high mobility group protein B1 nucleoplasmic shuttle and degradation via deacetylation in microglia.

Neuron. 2024 Aug 08. pii: S0896-6273(24)00537-3. [Epub ahead of print]

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism.

Caterina P Profaci, Sean S Harvey, Kaja Bajc, Tony Z Zhang, Danielle A Jeffrey, Alexander Z Zhang, Kelsey M Nemec, Hayk Davtyan, Carleigh A O'Brien, Gabriel L McKinsey, Aaron Longworth, Timothy P McMullen, Joia K Capocchi, Jessica G Gonzalez, Devon A Lawson, Thomas D Arnold, Dimitrios Davalos, Mathew Blurton-Jones, Fabrice Dabertrand, F Chris Bennett, Richard Daneman.

  Microglia, the resident immune cells of the central nervous system, are intimately involved in the brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, less is known about microglia-endothelial cell interactions in the healthy brain. To investigate the role of microglia at a healthy BBB, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed the BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for the maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism. This effect was independent from microglial depletion, suggesting that PLX5622 has off-target effects on brain vasculature.

Keywords:  CSF1R; LDLR; PLX5622; blood-brain barrier; cholesterol; endothelial cells; genetic microglial depletion; microglia; off-target effects; vasculature

DOI:  https://doi.org/10.1016/j.neuron.2024.07.015
J Neuroinflammation. 2024 Aug 11. 21(1): 200

The dopamine analogue CA140 alleviates AD pathology, neuroinflammation, and rescues synaptic/cognitive functions by modulating DRD1 signaling or directly binding to Abeta.

Sehyun Chae, Hyun-Ju Lee, Ha-Eun Lee, Jieun Kim, Yoo Joo Jeong, Yuxi Lin, Hye Yun Kim, Geoffray Leriche, Rachel S Ehrlich, Sascha Castro Lingl, Min-Duk Seo, Young-Ho Lee, Jerry Yang, Jae-Ick Kim, Hyang-Sook Hoe.

   BACKGROUND: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown.
METHODS: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted.
RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling.
CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

Keywords:  Aβ; CA140; Dopamine D1 receptor; LTP; Learning and memory; Reactive gliosis; Tau

DOI:  https://doi.org/10.1186/s12974-024-03180-x
Nat Commun. 2024 Aug 15. 15(1): 7028

C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model.

Nicole D Schartz, Heidi Y Liang, Klebea Carvalho, Shu-Hui Chu, Adrian Mendoza-Arvilla, Tiffany J Petrisko, Angela Gomez-Arboledas, Ali Mortazavi, Andrea J Tenner.

Alzheimer's disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. The complement pathway has been proposed as a therapeutic target. C5aR1 inhibition reduces plaque load, gliosis, and memory deficits in animal models, however, the cellular bases underlying this neuroprotection were unclear. Here, we show that the C5aR1 antagonist PMX205 improves outcomes in the Arctic48 mouse model of AD. A combination of single cell and single nucleus RNA-seq analysis of hippocampi derived from males and females identified neurotoxic disease-associated microglia clusters in Arctic mice that are C5aR1-dependent, while microglial genes associated with synapse organization and transmission and learning were overrepresented in PMX205-treated mice. PMX205 also reduced neurotoxic astrocyte gene expression, but clusters associated with protective responses to injury were unchanged. C5aR1 inhibition promoted mRNA-predicted signaling pathways between brain cell types associated with cell growth and repair, while suppressing inflammatory pathways. Finally, although hippocampal plaque load was unaffected, PMX205 prevented deficits in short-term memory in female Arctic mice. In conclusion, C5aR1 inhibition prevents cognitive loss, limits detrimental glial polarization while permitting neuroprotective responses, as well as leaving most protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for AD.

DOI: https://doi.org/10.1038/s41467-024-51163-6
Acta Neuropathol. 2024 Aug 16. 148(1): 21

Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease.

Shaoping Zhong, Yangye Lian, Binbin Zhou, Ruiqing Ren, Lewei Duan, Yuyin Pan, Yuchen Gong, Xiaoling Wu, Dengfeng Cheng, Puming Zhang, Boxun Lu, Xin Wang, Jing Ding.

  Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by the expansion of GGC trinucleotide repeats in NOTCH2NLC gene. Despite identifying uN2CpolyG, a toxic polyglycine (polyG) protein translated by expanded GGC repeats, the exact pathogenic mechanisms of NIID remain unclear. In this study, we investigated the role of polyG by expressing various forms of NOTCH2NLC in mice: the wild-type, the expanded form with 100 GGC repeats (either translating or not translating into uN2CpolyG), and the mutated form that encodes a pure polyG without GGC-repeat RNA and the C-terminal stretch (uN2CpolyG-dCT). Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and resulted in neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathologic lesions such as white-matter lesions, microgliosis, and astrogliosis. In contrast, expressing GGC-repeat RNA alone was non-pathogenic. Through bulk and single-nuclei RNA sequencing, we identified common molecular signatures linked to the expression of uN2CpolyG and uN2CpolyG-dCT, particularly the upregulation of inflammation and microglia markers, and the downregulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients using positron emission tomography, correlating with levels of white-matter atrophy. Furthermore, microglia ablation ameliorated neurodegenerative phenotypes and transcriptional alterations in uN2CpolyG-expressing mice but did not affect polyG inclusions. Together, these results demonstrate that polyG is crucial for the pathogenesis of NIID and highlight the significant role of microglia in polyG-induced neurodegeneration.

Keywords:  18-kD translocator protein; Microglia; Neurodegeneration; Neuronal intranuclear inclusion disease; Polyglycine

DOI:  https://doi.org/10.1007/s00401-024-02776-0
Cell Rep Med. 2024 Jul 31. pii: S2666-3791(24)00401-4. [Epub ahead of print] 101680

A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.

Francesca Fagiani, Edoardo Pedrini, Stefano Taverna, Elena Brambilla, Valentina Murtaj, Paola Podini, Francesca Ruffini, Erica Butti, Clarissa Braccia, Annapaola Andolfo, Roberta Magliozzi, Lena Smirnova, Tanja Kuhlmann, Angelo Quattrini, Peter A Calabresi, Daniel S Reich, Gianvito Martino, Paola Panina-Bordignon, Martina Absinta.

  The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.

Keywords:  SOX10; brain organoids; glia-microglia axis; hiPSC; multiple sclerosis; neuroinflammation; oligodendrocytes; single-cell genomics

DOI:  https://doi.org/10.1016/j.xcrm.2024.101680
bioRxiv. 2024 Jul 29. pii: 2024.07.27.605444. [Epub ahead of print]

Characterizing microglial signaling dynamics during inflammation using single-cell mass cytometry.

Sushanth Kumar, August D Kahle, Austin B Keeler, Eli R Zunder, Christopher D Deppmann.

  Microglia play a critical role in maintaining central nervous system (CNS) homeostasis and display remarkable plasticity in their response to inflammatory stimuli. However, the specific signaling profiles that microglia adopt during such challenges remain incompletely understood. Traditional transcriptomic approaches provide valuable insights, but fail to capture dynamic post-translational changes. In this study, we utilized time-resolved single-cell mass cytometry (CyTOF) to measure distinct signaling pathways activated in microglia upon exposure to bacterial and viral mimetics-lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly(I:C)), respectively. Furthermore, we evaluated the immunomodulatory role of astrocytes on microglial signaling in mixed cultures. Microglia or mixed cultures derived from neonatal mice were treated with LPS or Poly(I:C) for 48 hrs. Cultures were stained with a panel of 33 metal-conjugated antibodies targeting signaling and identity markers. High-dimensional clustering analysis was used to identify emergent signaling modules. We found that LPS treatment led to more robust early activation of pp38, pERK, pRSK, and pCREB compared to Poly(I:C). Despite these differences, both LPS and Poly(I:C) upregulated the classical activation markers CD40 and CD86 at later time-points. Strikingly, the presence of astrocytes significantly blunted microglial responses to both stimuli, particularly dampening CD40 upregulation. Our studies demonstrate that single-cell mass cytometry effectively captures the dynamic signaling landscape of microglia under pro-inflammatory conditions. This approach may pave the way for targeted therapeutic investigations of various neuroinflammatory disorders. Moreover, our findings underscore the necessity of considering cellular context, such as astrocyte presence, in interpreting microglial behavior during inflammation.

Keywords:  Astrocytes; CyTOF; Lipopolysaccharide (LPS); Mass Cytometry; Microglia; Neuroinflammation; Poly(I:C); Signaling Pathways

DOI:  https://doi.org/10.1101/2024.07.27.605444
bioRxiv. 2024 Jul 31. pii: 2024.07.30.605867. [Epub ahead of print]

Mechanism of neurodegeneration mediated by clonal inflammatory microglia.

Rocio Vicario, Stamatina Fragkogianni, Maria Pokrovskii, Carina Mayer, Estibaliz Lopez-Rodrigo, Yang Hu, Masato Ogishi, Araitz Alberdi, Ann Baako, Oyku Ay, Isabelle Plu, Véronique Sazdovitch, Sebastien Heritier, Fleur Cohen-Aubart, Natalia Shor, Makoto Miyara, Florence Nguyen-Khac, Agnes Viale, Ahmed Idbaih, Zahir Amoura, Marc K Rosenblum, Haochen Zhang, Elias-Ramzey Karnoub, Palash Sashittal, Akhil Jakatdar, Christine A Iacobuzio-Donahue, Omar Abdel-Wahab, Viviane Tabar, Nicholas D Socci, Olivier Elemento, Eli L Diamond, Bertrand Boisson, Jean-Laurent Casanova, Danielle Seilhean, Julien Haroche, Jean Donadieu, Frederic Geissmann.

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1 + microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1 + clones (p= 0.0003). Genetic lineage tracing of PU.1 + clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

DOI: https://doi.org/10.1101/2024.07.30.605867
Stem Cell Res Ther. 2024 Aug 13. 15(1): 258

Human brain organoids containing microglia that have arisen innately adapt to a β-amyloid challenge better than those in which microglia are integrated by co-culture.

Tyler J Wenzel, Joseph D Desjarlais, Darrell D Mousseau.

   BACKGROUND: Alzheimer disease (AD) is a heterogenous and multifactorial disease, and its pathology is partly driven by microglia and their activated phenotype. Brain organoids (BOs) are gaining prominence as a relevant model of the human brain for the study of AD; however, BOs are commonly devoid of microglia. To overcome this limitation, current protocols incorporate microglia through either (1) co-culture (BO co-culture), or (2) molecular manipulation at critical windows of BO development to have microglia arise innately (BO innate cultures). It is currently unclear whether the microglia incorporated into BOs by either of these two protocols differ in function.
METHODS: At in vitro day 90, BO innate cultures and BO-co-cultures were challenged with the AD-related β-amyloid peptide (Aβ) for up to 72 h. After Aβ challenge, BOs were collected for immunoblotting. Immunoblots compared immunodensity and protein banding of Aβ and ionized calcium-binding adapter molecule 1 (IBA1, a marker of microglial activation) in BOs. The translational potential of these observations was supported using 56 human cortical samples from neurocognitively normal donors and patients with early-onset AD and late-onset AD. Statistical analyses were conducted using the Kruskal-Wallis test, a two-way ANOVA, or a simple linear regression, and where applicable, followed by Dunn's or Sidak's test.
RESULTS: We show that BO co-cultures promote Aβ oligomerization as early as 24 h and this coincides with a significant increase in IBA1 levels. In contrast, the Aβs do not oligomerize in BO innate cultures and the IBA1 response was modest and only emerged after 48 h. In human cortical samples, we found IBA1 levels correlated with age at onset, age at death, and the putative diagnostic Aβ(1-42)/Aβ(1-40) ratio (particularly in their oligomeric forms) in a sex-dependent manner.
CONCLUSIONS: Our unique observations suggest that BOs with innate microglia model the response of a healthy brain to Aβ, and by extension the initial stages of Aβ challenge. It would be impossible to model these early stages of pathogenesis in BOs where microglia are already compromised, such as those with microglia incorporated by co-culture.

Keywords:  Alzheimer disease; Alzheimer’s disease; Autopsy brain; Aβ; Human brain; IBA1; Ionized calcium-binding adapter molecule 1; Microglial activation; Neuroinflammation

DOI:  https://doi.org/10.1186/s13287-024-03876-0
Res Sq. 2024 Aug 09. pii: rs.3.rs-4713316. [Epub ahead of print]

Microglial process convergence onto injured axonal swellings, a human postmortem brain tissue study.

Amanda L Logan-Wesley, Karen M Gorse, Audrey D Lafrenaye.

Traumatic brain injury (TBI) affects millions globally, with a majority of TBI cases being classified as mild, in which diffuse pathologies prevail. Two of the pathological hallmarks of TBI are diffuse axonal injury and microglial activation. While progress has been made investigating the breadth of TBI-induced axonal injury and microglial changes in rodents, the neuroinflammatory progression and interaction between microglia and injured axons following brain injury in humans is less well understood. Our group previously investigated microglial process convergence (MPC), in which processes of non-phagocytic microglia directly contact injured proximal axonal segments, in rats and micropigs acutely following TBI. These studies demonstrated that MPC occurred on injured axons in the micropig, but not in the rat, following diffuse TBI. While it has been shown that microglia co-exist and interact with injured axons in humans post-TBI, the occurrence of MPC has not been quantitatively measured in the human brain. Therefore, in the current study we sought to validate our pig findings in human postmortem tissue. We investigated MPC onto injured axonal swellings and intact myelinated fibers in cases from individuals that sustained a TBI and control human brain tissue using multiplex immunofluorescent histochemistry. We found an increase in MPC onto injured axonal swellings, consistent with our previous findings in micropigs, indicating that MPC is a clinically relevant phenomenon that warrants further investigation.

DOI: https://doi.org/10.21203/rs.3.rs-4713316/v1
J Vis Exp. 2024 Jul 26.

Assembling Retinal Organoids with Microglia.

Jia Xu, Si-Jian Yu, Zi-Bing Jin.

Due to the limited accessibility of the human retina, retinal organoids (ROs) are the best model for studying human retinal disease, which could reveal the mechanism of retinal development and the occurrence of retinal disease. Microglia (MG) are unique resident macrophages in the retina and central nervous system (CNS), serving crucial immunity functions. However, retinal organoids lack microglia since their differentiation origin is the yolk sac. The specific pathogenesis of microglia in these retinal diseases remains unclear; therefore, the establishment of a microglia-incorporated retinal organoid model turns out to be necessary. Here, we successfully constructed a co-cultured model of retinal organoids with microglia derived from human stem cells. In this article, we differentiated microglia and then co-cultured to retinal organoids in the early stage. As the incorporation of immune cells, this model provides an optimized platform for retinal disease modeling and drug screening to facilitate in-depth research on the pathogenesis and treatment of retinal and CNS-related diseases.

DOI: https://doi.org/10.3791/67016
CNS Neurosci Ther. 2024 Aug;30(8): e14913

Hyperglycemia-induced Sirt3 downregulation increases microglial aerobic glycolysis and inflammation in diabetic neuropathic pain pathogenesis.

Yongchang Li, Erliang Kong, Ruifeng Ding, Ruitong Chu, Jinfang Lu, Mengqiu Deng, Tong Hua, Mei Yang, Haowei Wang, Dashuang Chen, Honghao Song, Huawei Wei, Ping Zhang, Chaofeng Han, Hongbin Yuan.

   BACKGROUND: Hyperglycemia-induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear.
OBJECTIVE: To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia-induced neuroinflammation and DNP and to explore potential therapeutic interventions.
METHOD AND RESULTS: Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA-sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia-induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high-glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy-lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia-induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia-induced Sirt3 downregulation.
CONCLUSION: Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP.

Keywords:  Akt/FoxO1; Sirt3; diabetic neuropathic pain; glycolysis; metformin; neuroinflammation

DOI:  https://doi.org/10.1111/cns.14913
Glia. 2024 Aug 13.

Soluble TGF-β decoy receptor TGFBR3 exacerbates Alzheimer's disease pathology by modifying microglial function.

Lijun Zhou, Nan Wang, Wenzheng Feng, Xin Liu, Qiong Wu, Jiangxia Chen, Xinming Jiao, Xinyue Ning, Zhentong Qi, Zihua Xu, Xiaowen Jiang, Qingchun Zhao.

  Alzheimer's disease (AD) is a major cause of progressive dementia characterized by memory loss and progressive neurocognitive dysfunction. However, the molecular mechanisms are not fully understood. To elucidate the molecular mechanism contributing to AD, an integrated analytical workflow was deployed to identify pivotal regulatory target within the RNA-sequencing (RNA-seq) data of the temporal cortex from AD patients. Soluble transforming growth factor beta receptor 3 (sTGFBR3) was identified as a critical target in AD, which was abnormally elevated in AD patients and AD mouse models. We then demonstrated that sTGFBR3 deficiency restored spatial learning and memory deficits in amyloid precursor protein (APP)/PS1 and streptozotocin (STZ)-induced neuronal impairment mice after its expression was disrupted by a lentiviral (LV) vector expressing shRNA. Mechanistically, sTGFBR3 deficiency augments TGF-β signaling and suppressing the NF-κB pathway, thereby reduced the number of disease-associated microglia (DAMs), inhibited proinflammatory activity and increased the phagocytic activity of DAMs. Moreover, sTGFBR3 deficiency significantly mitigated acute neuroinflammation provoked by lipopolysaccharide (LPS) and alleviated neuronal dysfunction induced by STZ. Collectively, these results position sTGFBR3 as a promising candidate for therapeutic intervention in AD.

Keywords:  APP/PS1 mice; Alzheimer's disease; RNA‐seq; microglia; sTGFBR3

DOI:  https://doi.org/10.1002/glia.24606
Front Cell Dev Biol. 2024 ;12 1421191

Role of microglia in diabetic neuropathic pain.

Qian Wang, Yilin Xie, Shichao Ma, Hongliang Luo, Yue Qiu.

  Approximately one-third of the patients with diabetes worldwide suffer from neuropathic pain, mainly categorized by spontaneous and stimulus-induced pain. Microglia are a class of immune effector cells residing in the central nervous system and play a pivotal role in diabetic neuropathic pain (DNP). Microglia specifically respond to hyperglycemia along with inflammatory cytokines and adenosine triphosphate produced during hyperglycemic damage to nerve fibers. Because of the presence of multiple receptors on the microglial surface, microglia are dynamically and highly responsive to their immediate environment. Following peripheral sensitization caused by hyperglycemia, microglia are affected by the cascade of inflammatory factors and other substances and respond accordingly, resulting in a change in their functional state for DNP pathogenesis. Inhibition of receptors such as P2X reporters, reducing cytokine expression levels in the microglial reactivity mechanisms, and inhibiting their intracellular signaling pathways can effectively alleviate DNP. A variety of drugs attenuate DNP by inhibiting the aforementioned processes induced by microglial reactivity. In this review, we summarize the pathological mechanisms by which microglia promote and maintain DNP, the drugs and therapeutic techniques available, and the latest advances in this field.

Keywords:  diabetes; mechanism; microglia; neuropathic pain; treatment

DOI:  https://doi.org/10.3389/fcell.2024.1421191
Front Cell Neurosci. 2024 ;18 1429977

Neuroinflammation in Parkinson's disease: focus on the relationship between miRNAs and microglia.

Ke Xu, Yuan Li, Yan Zhou, Yu Zhang, Yue Shi, Chengguang Zhang, Yan Bai, Shun Wang.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder that affects the central nervous system (CNS). Neuroinflammation is a crucial factor in the pathological advancement of PD. PD is characterized by the presence of activated microglia and increased levels of proinflammatory factors, which play a crucial role in its pathology. During the immune response of PD, microglia regulation is significantly influenced by microRNA (miRNA). The excessive activation of microglia, persistent neuroinflammation, and abnormal polarization of macrophages in the brain can be attributed to the dysregulation of certain miRNAs. Additionally, there are miRNAs that possess the ability to inhibit neuroinflammation. miRNAs, which are small non-coding epigenetic regulators, have the ability to modulate microglial activity in both normal and abnormal conditions. They also have a significant impact on promoting communication between neurons and microglia.

Keywords:  Parkinson’s disease (PD); microRNA (miRNA); microglia; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.3389/fncel.2024.1429977
J Adv Res. 2024 Aug 12. pii: S2090-1232(24)00359-X. [Epub ahead of print]

Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction.

Yin Li, Hang Zhou, Xuchao He, Lingji Jin, Yuhan Zhu, Libin Hu, Majing Feng, Jun Zhu, Liang Wang, Yonghe Zheng, Shiwei Li, Zhiyuan Yan, Peili Cen, Junwen Hu, Zihang Chen, Xiaobo Yu, Xiongjie Fu, Chaoran Xu, Shenglong Cao, Yang Cao, Gao Chen, Lin Wang.

   INTRODUCTION: Intracerebral haemorrhage (ICH) is a devastating disease that leads to severe neurological deficits. Microglia are the first line of defence in the brain and play a crucial role in neurological recovery after ICH, whose activities are primarily driven by glucose metabolism. However, little is known regarding the status of glucose metabolism in microglia and its interactions with inflammatory responses after ICH.
OBJECTIVES: This study investigated microglial glycolysis and its mechanistic effects on microglial inflammation after ICH.
METHODS: We explored the status of glucose metabolism in the ipsilateral region and in fluorescence-activated-cell-sorting-isolated (FACS-isolated) microglia via 2-deoxy-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) analyses and gamma emission, respectively. Energy-related targeted metabolomics, along with 13C-glucose isotope tracing, was utilised to analyse glycolytic products in microglia. Mitochondrial membrane potential and mitochondrial reactive oxygen species (MitoROS) accumulation was assessed by flow cytometry. Behavioural, western blotting, gene regulation, and enzymatic activity analyses were conducted with a focus on microglia.
RESULTS: Neurological dysfunction was strongly correlated with decreased FDG-PET signals in the perihaematomal region, where microglial uptake of FDG was reduced. The decreased quantity of glucose-6-phosphate (G-6-P) in microglia was attributed to the downregulation of glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Enhanced inflammatory responses were driven by HK2 suppression via decreased mitochondrial membrane potential, which could be rescued by MitoROS scavengers. HK inhibitors aggravated neurological injury by suppressing FDG uptake and enhancing microglial inflammation in ICH mice.
CONCLUSION: These findings indicate an unexpected metabolic status in pro-inflammatory microglia after ICH, consisting of glycolysis impairment caused by the downregulation of GLUT1 and HK2. Additionally, HK2 suppression promotes inflammatory responses by disrupting mitochondrial function, providing insight into the mechanisms by which inflammation may be facilitated after ICH and indicating that metabolic enzymes as potential targets for ICH treatment.

Keywords:  Glycolysis; Hexokinase 2; Inflammation; Intracerebral haemorrhage; Microglia; Mitochondria

DOI:  https://doi.org/10.1016/j.jare.2024.08.016
bioRxiv. 2024 Aug 09. pii: 2024.08.08.607229. [Epub ahead of print]

Epigenetic heterogeneity shapes the transcriptional landscape of regional microglia.

Alexander V Margetts, Samara J Vilca, Florence Bourgain-Guglielmetti, Luis M Tuesta.

Microglia, the innate immune cells in the central nervous system, exhibit distinct transcriptional profiles across brain regions that are important for facilitating their specialized function. There has been recent interest in identifying the epigenetic modifications associated with these distinct transcriptional profiles, as these may improve our understanding of the underlying mechanisms governing the functional specialization of microglia. One obstacle to achieving this goal is the large number of microglia required to obtain a genome-wide profile for a single histone modification. Given the cellular and regional heterogeneity of the brain, this would require pooling many samples which would impede biological applications that are limited by numbers of available animals. To overcome this obstacle, we have adapted a method of chromatin profiling known as Cleavage Under Targets and Tagmentation (CUT&Tag-Direct) to profile histone modifications associated with regional differences in gene expression throughout the brain reward system. Consistent with previous studies, we find that transcriptional profiles of microglia vary by brain region. However, here we report that these regional differences also exhibit transcriptional network signatures specific to each region. Additionally, we find that these region-dependent network signatures are associated with differential deposition of H3K27ac and H3K7me3, and while the H3K27me3 landscape is remarkably stable across brain regions, the H3K27ac landscape is most consistent with the anatomical location of microglia which explain their distinct transcriptional profiles. Altogether, these findings underscore the established role of H3K27me3 in cell fate determination and support the active role of H3K27ac in the dynamic regulation of microglial gene expression. In this study, we report a molecular and computational framework that can be applied to improve our understanding of the role of epigenetic regulation in microglia in both health and disease, using as few as 2,500 cells per histone mark.

DOI: https://doi.org/10.1101/2024.08.08.607229
bioRxiv. 2024 Aug 06. pii: 2024.08.06.606815. [Epub ahead of print]

Sphingosine-1-phosphate signaling regulates the ability of Müller glia to become neurogenic, proliferating progenitor-like cells.

Olivia Taylor, Nicholas DeGroff, Heithem El-Hodiri, Chengyu Gao, Andy J Fischer.

The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. S1PR1 is highly expressed by resting MG and is rapidly downregulated following acute retinal damage. Drug treatments that activate S1PR1 or increase levels of S1P suppressed the formation of MGPCs, whereas treatments that inhibit S1PR1 or decreased levels of S1P stimulated the formation of MGPCs. Inhibition of S1PR1 or SPHK1 significantly enhanced the neuronal differentiation of the progeny of MGPCs. Further, ablation of microglia from the retina, wherein the formation of MGPCs in damaged retinas is impaired, has a significant impact upon expression patterns of S1P-related genes in MG. Inhibition of S1PR1 and SPHK1 partially rescued the formation of MGPCs in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs and activation of S1P signaling depends, in part, on signals produced by reactive microglia.

DOI: https://doi.org/10.1101/2024.08.06.606815
Life Sci. 2024 Aug 12. pii: S0024-3205(24)00563-0. [Epub ahead of print] 122973

Androgen deprivation exacerbates AD pathology by promoting the loss of microglia in an age-dependent manner.

Jiaxin Cao, Haichao Chen, Yishu Zhang, Yiting Kang, Siwei Zhou, Zirui Liao, Liping Gao, Jie Yin, Yuhong Jing.

   AIMS: Microglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD.
METHODS AND KEY FINDINGS: To create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aβ) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aβ plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aβ1-42-induced apoptosis.
SIGNIFICANCE: These findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.

Keywords:  AD; Androgen; Apoptosis; Aβ; Cell proliferation; Microglia

DOI:  https://doi.org/10.1016/j.lfs.2024.122973
Neurosci Biobehav Rev. 2024 Aug 12. pii: S0149-7634(24)00317-8. [Epub ahead of print] 105848

Microglial activation and polarization in type 2 diabetes-related cognitive impairment: A focused review of pathogenesis.

Yue Tian, Guangchan Jing, Mei Ma, Ruiying Yin, Mengren Zhang.

  Microglia, as immune cells in the central nervous system, are closely related to cognitive impairment associated with type 2 diabetes (T2D). Preliminary explorations have investigated the relationship between T2D-related cognitive impairment and the activation and polarization of microglia. This review summarizes the potential mechanisms of microglial activation and polarization in the context of T2D. It discusses central inflammatory responses, neuronal apoptosis, amyloid-β deposition, and abnormal phosphorylation of Tau protein mediated by microglial activation and polarization, exploring the connections between microglial activation and polarization and T2D-related cognitive impairment from multiple perspectives. Additionally, this review provides references for future treatment targeting microglia in T2D-related cognitive impairment and for clinical translation.

Keywords:  Amyloid-β; Clinical translation; Inflammatory responses; Microglia; Neuronal apoptosis; Tau protein; Type 2 diabetes-related cognitive impairment

DOI:  https://doi.org/10.1016/j.neubiorev.2024.105848
Front Pharmacol. 2024 ;15 1450704

Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.

Xiaoming Liu, Yiwen Li, Liting Huang, Yingyan Kuang, Xiaoxiong Wu, Xiangqiong Ma, Beibei Zhao, Jiao Lan.

  The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.

Keywords:  ATP; P2X7R; microglia; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.3389/fphar.2024.1450704
Metab Brain Dis. 2024 Aug 13.

Bulk-RNA and single-nuclei RNA seq analyses reveal the role of lactate metabolism-related genes in Alzheimer's disease.

Hanjie Liu, Xiaohong Yi, Maochun You, Hui Yang, Siyu Zhang, Sihan Huang, Lushuang Xie.

  Dysfunctional lactate metabolism in the brain has been implicated in neuroinflammation, Aβ deposition, and cell disturbance, all of which play a significant role in the pathogenesis of Alzheimer's disease (AD). In this study, we aimed to investigate the lactate metabolism-related genes (LMRGs) in AD via an integrated bulk RNA and single-nuclei RNA sequencing (snRNA-seq) analysis, with a specific focus on microglia. We obtained 26 HC and 24 AD snRNA-seq samples originated from human prefrontal cortex in Gene Expression Omnibus (GEO) database and collected 873 LMRGs from three databases, namely MSigDB, The Human Protein Atlas and GeneCards. Bulk RNA was analyzed with LMRG characteristics in AD by using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), the protein-protein interaction (PPI), CytoHubba-MCC, Support Vector Machine (SVM) algorithms analyses. Then we conducted the Receiver Operating Characteristic (ROC) curve, correlation, and connection network analyses for biomarkers. Their differential expression validation was performed using AlzData database. The single-nuclei RNA analysis of microglia was applied to identify hub genes and pathways using cell-cell communication analysis and high dimensional Weighted Gene Co-Expression Network Analysis (hdWGCNA). Support Vector Machine (SVM) algorithm showed an AUC of 0.967, a sensitivity of 93.30% and a specificity of 100.00%. Our analysis identified biomarkers with LMRG characteristics, namely INSR, CDKL1, and PNISR. ROC analysis revealed that each of these biomarkers exhibited excellent diagnostic potential, as evidenced by their respective area under the curve (AUC) values: INSR (AUC: 0.679), CDKL1 (AUC: 0.788), and PNISR (AUC: 0.724). Correlation analysis showed that biomarkers exhibited a positive correlation with each other. Connection network illustrated their shared biological processes: aging, phosphorylation, metabolic process, and apoptosis. Cell-cell communication analysis revealed that GALECTIN signaling pathway was exclusively expressed in AD microglia, and only LGALS9 exhibited significant overexpression. HdWGCNA identified FTH1 as a hub gene enriched in ferroptosis and mineral absorption pathways within microglia. The roles of INSR, CDKL1, PNISR, LGALS9, and FTH1 should be taken into account to enhance our understanding of lactate metabolism in the context of AD.

Keywords:  Alzheimer’s disease; Lactate metabolism; Microglia; snRNA transcriptomics

DOI:  https://doi.org/10.1007/s11011-024-01396-7
J Cell Physiol. 2024 Aug 11. e31364

SIRT2 regulates high mobility group protein B1 nucleoplasmic shuttle and degradation via deacetylation in microglia.

Wan-Qun Xing, Xian-Ji Piao, Qi Han, Hui-Ying Shi, Wen-Cong Wu, Fan Si, Jing-Jing Lu, Tie-Zhong Zhou, Jing-Ru Guo, Shi-Ze Li, Bin Xu.

  High mobility group protein B1 (HMGB1) acts as a pathogenic inflammatory response to mediate ranges of conditions such as epilepsy, septic shock, ischemia, traumatic brain injury, Parkinson's disease, Alzheimer's disease and mass spectrometry. HMGB1 promotes inflammation during sterile and infectious damage and plays a crucial role in disease development. Mobilization from the nucleus to the cytoplasm is the first important step in the release of HMGB1 from activated immune cells. Here, we demonstrated that Sirtuin 2 (SIRT2) physically interacts with and deacetylates HMGB1 at 43 lysine residue at nuclear localization signal locations, strengthening its interaction with HMGB1 and causing HMGB1 to be localized in the cytoplasm. These discoveries are the first to shed light on the SIRT2 nucleoplasmic shuttle, which influences HMGB1 and its degradation, hence revealing novel therapeutic targets and avenues for neuroinflammation treatment.

Keywords:  SIRT2; deacetylation; high mobility group protein B1; neuroinflammation; nucleoplasmic shuttle

DOI:  https://doi.org/10.1002/jcp.31364