bims-microg 2024-09-01 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–09–01
27 papers selected by
Marcus Karlstetter, Universität zu Köln

Microglial activation in CKD-associated cognitive decline.
Suppression of inner blood-retinal barrier breakdown and pathogenic Müller glia activation in ischemia retinopathy by myeloid cell depletion.
Switch to phagocytic microglia by CSFR1 inhibition drives amyloid-beta clearance from glutamatergic terminals rescuing LTP in acute hippocampal slices.
N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy.
TREM2-dependent activation of microglial cell protects photoreceptor cell during retinal degeneration via PPARγ and CD36.
Microglial cGAS-STING signaling underlies glaucoma pathogenesis.
Lactic acid regulates lipid droplet aggregation through a microglia-neuron axis in neuroinflammation.
Aged-Related Changes in Microglia and Neurodegenerative Diseases: Exploring the Connection.
Severe hypoglycaemia-induced microglial inflammation damages microvascular endothelial cells, leading to retinal destruction.
Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation.
Aerobic exercise modulates RIPK1-mediated MAP3K5/JNK and NF-κB pathways to suppress microglia activation and neuroinflammation in the hippocampus of D-gal-induced accelerated aging mice.
A radioligand for in vitro autoradiography of CSF1R in post-mortem CNS tissues.
Old Age Exacerbates White Matter Neuroinflammation and Cognitive Deficits Following Closed-Head Injury, Particularly in Female Mice.
Glial reactivity is linked to synaptic dysfunction across the aging and Alzheimer's disease spectrum.
A Neuronal Activity-Boosting Microglial Function in Post-Anesthetic Emergence: How Microglial-Neuronal Crosstalk May Alter States of Consciousness.
Electroacupuncture regulates glucose metabolism by inhibiting SGLT1 levels, inhibiting microglial polarization, and alleviating Parkinson's disease.
Effects of social dominance and acute social stress on morphology of microglia and structural integrity of the medial prefrontal cortex.
CD8+ T cells exacerbate AD-like symptoms in mouse model of amyloidosis.
Amyloid-β-activated microglia can induce compound proteinopathies.
Exosomal miRNA-21 derived from umbilical cord mesenchymal stem cells inhibits microglial overactivation to counteract nerve damage.
Microglia: The Drunken Gardeners of Early Adversity.
Increased Pan-Type, A1-Type, and A2-Type Astrocyte Activation and Upstream Inflammatory Markers Are Induced by the P2X7 Receptor.
The Immunomodulatory Effect of Silver Nanoparticles in a Retinal Inflammatory Environment.
Tetramerization of PKM2 Alleviates Traumatic Brain Injury by Ameliorating Mitochondrial Damage in Microglia.
Microglia are Required for Developmental Specification of AgRP Innervation in the Hypothalamus of Offspring Exposed to Maternal High Fat Diet During Lactation.
Trazodone counteracts the response of microglial cells to inflammatory stimuli.
Purinergic exposure induces epigenomic and transcriptomic-mediated preconditioning resembling epilepsy-associated microglial states.

Nat Rev Nephrol. 2024 Aug 27.

Microglial activation in CKD-associated cognitive decline.

Susan J Allison.

DOI: https://doi.org/10.1038/s41581-024-00891-5
J Neuroinflammation. 2024 Aug 24. 21(1): 210

Suppression of inner blood-retinal barrier breakdown and pathogenic Müller glia activation in ischemia retinopathy by myeloid cell depletion.

Lingli Zhou, Zhenhua Xu, Haining Lu, Hongkwan Cho, Yangyiran Xie, Grace Lee, Kaoru Ri, Elia J Duh.

  Ischemic retinopathies including diabetic retinopathy are major causes of vision loss. Inner blood-retinal barrier (BRB) breakdown with retinal vascular hyperpermeability results in macular edema. Although dysfunction of the neurovascular unit including neurons, glia, and vascular cells is now understood to underlie this process, there is a need for fuller elucidation of the underlying events in BRB dysfunction in ischemic disease, including a systematic analysis of myeloid cells and exploration of cellular cross-talk. We used an approach for microglia depletion with the CSF-1R inhibitor PLX5622 (PLX) in the retinal ischemia-reperfusion (IR) model. Under non-IR conditions, PLX treatment successfully depleted microglia in the retina. PLX suppressed the microglial activation response following IR as well as infiltration of monocyte-derived macrophages. This occurred in association with reduction of retinal expression of chemokines including CCL2 and the inflammatory adhesion molecule ICAM-1. In addition, there was a marked suppression of retinal neuroinflammation with reduction in expression of IL-1b, IL-6, Ptgs2, TNF-a, and Angpt2, a protein that regulates BRB permeability. PLX treatment significantly suppressed inner BRB breakdown following IR, without an appreciable effect on neuronal dysfunction. A translatomic analysis of Müller glial-specific gene expression in vivo using the Ribotag approach demonstrated a strong suppression of Müller cell expression of multiple pro-inflammatory genes following PLX treatment. Co-culture studies of Müller cells and microglia demonstrated that activated microglia directly upregulates Müller cell-expression of these inflammatory genes, indicating Müller cells as a downstream effector of myeloid cells in retinal IR. Co-culture studies of these two cell types with endothelial cells demonstrated the ability of both activated microglia and Müller cells to compromise EC barrier function. Interestingly, quiescent Müller cells enhanced EC barrier function in this co-culture system. Together this demonstrates a pivotal role for myeloid cells in inner BRB breakdown in the setting of ischemia-associated disease and indicates that myeloid cells play a major role in iBRB dysregulation, through direct and indirect effects, while Müller glia participate in amplifying the neuroinflammatory effect of myeloid cells.

Keywords:  Blood-retinal barrier; Csf1r; Macrophages; Microglia; Müller glia; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-024-03190-9
Transl Psychiatry. 2024 Aug 23. 14(1): 338

Switch to phagocytic microglia by CSFR1 inhibition drives amyloid-beta clearance from glutamatergic terminals rescuing LTP in acute hippocampal slices.

Gaia Piccioni, Nunzia Maisto, Asia d'Ettorre, Georgios Strimpakos, Robert Nisticò, Viviana Triaca, Dalila Mango.

Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aβ accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aβ-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aβ. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aβ from glutamatergic terminals. We believe that the selective pruning of Aβ-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.

DOI: https://doi.org/10.1038/s41398-024-03019-2
Proc Natl Acad Sci U S A. 2024 Sep 03. 121(36): e2410564121

N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy.

Shenjia Gao, Ruling Shen, Jie Li, Yi Jiang, Hao Sun, Xinyi Wu, Xiya Li, Changhong Miao, Miao He, Jun Wang, Wankun Chen.

  Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABABR1 as a key downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABABR1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABABR1 expression through mRNA acetylation, leading to cognitive dysfunction.

Keywords:  GABABR1; NAT10; cognitive dysfunction; microglia; sepsis-associated encephalopathy

DOI:  https://doi.org/10.1073/pnas.2410564121
Cell Death Dis. 2024 Aug 26. 15(8): 623

TREM2-dependent activation of microglial cell protects photoreceptor cell during retinal degeneration via PPARγ and CD36.

Wenchuan Zhou, Jincan He, Guiyan Shen, Ya Liu, Peiquan Zhao, Jing Li.

Retinal degeneration is a collection of devastating conditions with progressive loss of vision which often lead to blindness. Research on retinal microglial cells offers great therapeutic potential in deterring the progression of degeneration. This study explored the mechanisms underlying the TREM2-mediated protective function of activated microglial cells during retinal degeneration. N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was established in C57BL/6 J (WT) and Trem2 knockout (Trem2-/-) mice. We discovered that MNU treatment led to the concurrent processes of photoreceptor apoptosis and microglia infiltration. A significant upregulation of disease-associated microglia signature genes was observed during photoreceptor degeneration. Following MNU treatment, Trem2-/- mice showed exacerbated photoreceptor cell death, decreased microglia migration and phagocytosis, reduced microglial PPARγ activation and CD36 expression. Pharmaceutical activation of PPARγ promoted microglial migration, ameliorated photoreceptor degeneration and restored CD36 expression in MNU-treated Trem2-/- mice. Inhibition of CD36 activity worsened photoreceptor degeneration in MNU-treated WT mice. Our findings suggested that the protective effect of microglia during retinal degeneration was dependent on Trem2 expression and carried out via the activation of PPARγ and the consequent upregulation of CD36 expression. Our study linked TREM2 signaling with PPARγ activation, and provided a potential therapeutic target for the management of retinal degeneration.

DOI: https://doi.org/10.1038/s41419-024-07002-z
Proc Natl Acad Sci U S A. 2024 Sep 03. 121(36): e2409493121

Microglial cGAS-STING signaling underlies glaucoma pathogenesis.

Yutong Liu, Ailian Wang, Chen Chen, Qian Zhang, Qin Shen, Dan Zhang, Xueqi Xiao, Shasha Chen, Lili Lian, Zhenmin Le, Shengduo Liu, Tingbo Liang, Qinxiang Zheng, Pinglong Xu, Jian Zou.

  Characterized by progressive degeneration of retinal ganglion cells (RGCs) and vision loss, glaucoma is the primary cause of irreversible blindness, incurable and affecting over 78 million patients. However, pathogenic mechanisms leading to glaucoma-induced RGC loss are incompletely understood. Unexpectedly, we found that cGAS-STING (2'3'-cyclic GMP-AMP-stimulator of interferon genes) signaling, which surveils displaced double-stranded DNA (dsDNA) in the cytosol and initiates innate immune responses, was robustly activated during glaucoma in retinal microglia in distinct murine models. Global or microglial deletion of STING markedly relieved glaucoma symptoms and protected RGC degeneration and vision loss, while mice bearing genetic cGAS-STING supersensitivity aggravated retinal neuroinflammation and RGC loss. Mechanistically, dsDNA from tissue injury activated microglial cGAS-STING signaling, causing deleterious macroglia reactivity in retinas by cytokine-mediated microglia-macroglia interactions, progressively driving apoptotic death of RGCs. Remarkably, preclinical investigations of targeting cGAS-STING signaling by intraocular injection of TBK1i or anti-IFNAR1 antibody prevented glaucoma-induced losses of RGCs and vision. Therefore, we unravel an essential role of cGAS-STING signaling underlying glaucoma pathogenesis and suggest promising therapeutic strategies for treating this devastating disease.

Keywords:  cGAS–STING; glaucoma; microglia; neuroinflammation; vision loss

DOI:  https://doi.org/10.1073/pnas.2409493121
J Lipid Res. 2024 Aug 23. pii: S0022-2275(24)00134-2. [Epub ahead of print] 100629

Lactic acid regulates lipid droplet aggregation through a microglia-neuron axis in neuroinflammation.

Zhuoqing Lan, Shukai Lv, Ziyi Ge, Bing Zhao, Leilei Li, Caixia Li.

  Neuroinflammation, marked by the release of pro-inflammatory cytokines and resulting neuronal death, is a multifaceted process extending beyond traditional inflammatory pathways. Microglia, primary cells in the inflammatory response, rapidly activate during neuroinflammation and produce pro-inflammatory and cytotoxic factors that affect neuronal function. Recent evidence highlights the significant role of abnormal lipid droplet (LD) deposition in the pathogenesis of neuroinflammation. While microglia are known to influence LD aggregation during neuroinflammation, the regulatory mechanism within neurons is not well understood. Our study demonstrates that lipopolysaccharide (LPS)-activated microglia induce the accumulation of LD in neurons, identifying microglial-derived lactic acid as a key mediator in this process. Excessive lipid accumulation threatens neuronal function, a phenomenon reversed by eliminating microglia. These findings, corroborated in both in vitro and in vivo settings and supported by RNA sequencing, deepen our understanding of neuronal lipid metabolism and suggest potential targets for therapeutic strategies against acute neuroinflammation.

Keywords:  Microglia; RNA sequencing; lactic acid; lipid droplet; neuroinflammation; neuron

DOI:  https://doi.org/10.1016/j.jlr.2024.100629
Biomedicines. 2024 Aug 02. pii: 1737. [Epub ahead of print]12(8):

Aged-Related Changes in Microglia and Neurodegenerative Diseases: Exploring the Connection.

Borrajo Ana.

  Microglial cells exhibit properties akin to macrophages, thereby enabling them to support and protect the central nervous system environment. Aging induces alterations in microglial polarization, resulting in a shift toward a neurotoxic phenotype characterized by increased expression of pro-inflammatory markers. Dysregulation of microglial cells' regulatory pathways and interactions with neurons contribute to chronic activation and neurodegeneration. A better understanding of the involvement of microglia in neurodegenerative diseases such as Alzheimer's and Parkinson's is a critical topic for studying the role of inflammatory responses in disease progression. Furthermore, the metabolic changes in aged microglia, including the downregulation of oxidative phosphorylation, are discussed in this review. Understanding these mechanisms is crucial for developing better preventive and therapeutic strategies.

Keywords:  aging; inflammation; microglia; neurodegenetrative diseases; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines12081737
Diab Vasc Dis Res. 2024 Jul-Aug;21(4):21(4): 14791641241278506

Severe hypoglycaemia-induced microglial inflammation damages microvascular endothelial cells, leading to retinal destruction.

Yuxin Hu, Zhen Li, Hongxue Li, Qian Xu, Chengye Xu, Wenjian Lin, Xuefei Ma, Ming Hao, Hongyu Kuang.

  Human microglia (HMC) are stress-induced inflammatory cells of the retina. It is unknown whether severe hypoglycaemia causes inflammation in microglia, affects the permeability of human retinal microvascular endothelial cells (HRMECs), and causes retinal damage. This study aimed to explore the effects of severe hypoglycaemia on retinal microglial inflammation and endothelial cell permeability and evaluate the damage caused by hypoglycaemia to the retina. The CCK-8 assay was used to measure cell viability. Western blotting was used to detect IL-1β, IL-6, TNF- α, claudin-1, and occludin expression. ELISA was used to detect IL-1β, IL-6, and TNF- α. Transmission electron microscopy (TEM) and haematoxylin and eosin staining were used to observe the retinal structure. Immunohistochemistry and immunofluorescence staining assays were also used to detect IL-1β, IL-6, TNF- α, claudin-1, and occludin expression. Severe hypoglycaemia promoted inflammation in HMC3 cells. Inflammation caused by hypoglycaemia leads to the decreased expression of tight junction proteins. In vivo, severe hypoglycaemia induced structural damage to the retina, increased the expression of inflammatory factors, and decreased the expression of tight junction proteins. Our results suggest that severe hypoglycaemia leads to acute retinal inflammation, affecting the permeability of HRMECs and causing retinal damage.

Keywords:  Severe hypoglycaemia; human microglia; human retinal microvascular endothelial cells; inflammation; retinal damage

DOI:  https://doi.org/10.1177/14791641241278506
Cell Mol Biol Lett. 2024 Aug 28. 29(1): 114

Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation.

Yuhua Chen, Wei He, Junlin Qiu, Yangyang Luo, Chenlong Jiang, Feng Zhao, Hong Wei, Jiao Meng, Tianlin Long, Xin Zhang, Lingjian Yang, Quanhua Xu, Juning Wang, Chi Zhang.

   BACKGROUND: Stroke is a type of acute brain damage that can lead to a series of serious public health challenges. Demonstrating the molecular mechanism of stroke-related neural cell degeneration could help identify a more efficient treatment for stroke patients. Further elucidation of factors that regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may lead to a promising strategy for treating neuroinflammation after ischaemic stroke. In this study, we investigated the possible role of pterostilbene (PTS) in Nrf1 regulation in cell and animal models of ischaemia stroke.
METHODS: We administered PTS, ITSA1 (an HDAC activator) and RGFP966 (a selective HDAC3 inhibitor) in a mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and a model of microglial oxygen‒glucose deprivation/reperfusion (OGD/R). The brain infarct size, neuroinflammation and microglial availability were also determined. Dual-luciferase reporter, Nrf1 protein stability and co-immunoprecipitation assays were conducted to analyse histone deacetylase 3 (HDAC3)/Nrf1-regulated Nrf1 in an OGD/R-induced microglial injury model.
RESULTS: We found that PTS decreased HDAC3 expression and activity, increased Nrf1 acetylation in the cell nucleus and inhibited the interaction of Nrf1 with p65 and p65 accumulation, which reduced infarct volume and neuroinflammation (iNOS/Arg1, TNF-α and IL-1β levels) after ischaemic stroke. Furthermore, the CSF1R inhibitor PLX5622 induced elimination of microglia and attenuated the therapeutic effect of PTS following MCAO/R. In the OGD/R model, PTS relieved OGD/R-induced microglial injury and TNF-α and IL-1β release, which were dependent on Nrf1 acetylation through the upregulation of HDAC3/Nrf1 signalling in microglia. However, the K105R or/and K139R mutants of Nrf1 counteracted the impact of PTS in the OGD/R-induced microglial injury model, which indicates that PTS treatment might be a promising strategy for ischaemia stroke therapy.
CONCLUSION: The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of natural products such as PTS.

Keywords:  HDAC3; Ischaemic stroke; Neuroinflammation; Nrf1 acetylation; PTS

DOI:  https://doi.org/10.1186/s11658-024-00634-1
Physiol Behav. 2024 Aug 23. pii: S0031-9384(24)00224-5. [Epub ahead of print]286 114676

Aerobic exercise modulates RIPK1-mediated MAP3K5/JNK and NF-κB pathways to suppress microglia activation and neuroinflammation in the hippocampus of D-gal-induced accelerated aging mice.

Yang Liu, Xiaokang Meng, Changfa Tang, Lan Zheng, Kun Tao, Wen Guo.

  Microglia activation-induced neuroinflammation is a risk factor for cognitive dysfunction in the hippocampus during the early stages of neurodegenerative diseases. Exercise is an intrinsic remedy that plays a crucial role in enhancing the survival of neurons and reducing neuroinflammation in the brain. Among these theories, alterations in intracellular signaling pathways associated with neuronal growth and inflammation have been emphasized. Based on these observations and recent evidence demonstrating the beneficial effects of exercise on suppressing brain inflammation in the elderly, we examined cellular signaling pathways in the hippocampal formation of D-galactose-induced accelerated aging mice that underwent 8 weeks of treadmill exercise. To accomplish this, we utilized immunohistochemistry and Western blotting to detect the expression of hippocampal proteins, and qPCR to detect the expression of mRNA. We found that aerobic exercise significantly promoted the survival of hippocampal neurons, inhibited microglia activation, and decreased the expression of inflammatory cytokines TNF-α, IL-1α, IL-1β, and chemokines CXCL-1, CXCR-2 in D-galactose model mice. Furthermore, exercise contributed to decreasing the microglia activation marker Iba1-positive cell count and average optical density and increasing the number of NeuN-immunopositive cells. Exercise also reduced RIPK1 and MAP3K5 expression in the hippocampus. Surprisingly, aerobic exercise significantly decreased the expression ratios of p-p65/p65, p-IκBα/IκBα, and p-JNK/JNK. Therefore, we hypothesized that exercise has an anti-inflammatory effect on the hippocampus of mice in the D-galactose-induced aging model. This effect may be attributed to the ability of aerobic exercise to down-regulate the RIPK1-mediated NF-κB and JNK pathways.

Keywords:  Exercise; Hippocampus; Inflammation; JNK; MAP3K5; RIPK1

DOI:  https://doi.org/10.1016/j.physbeh.2024.114676
EJNMMI Res. 2024 Aug 26. 14(1): 76

A radioligand for in vitro autoradiography of CSF1R in post-mortem CNS tissues.

Catherine A Foss, Ravi Naik, Deepankar Das, Hyojin Cha, Il Minn, Andrew Hall, Paige Finley, Sophia Jiang Wu, Yong Du, Robert F Dannals, Martin G Pomper, Andrew G Horti.

   BACKGROUND: Reactive microglia and recruited peripheral macrophages contribute to the pathogenesis of Alzheimer's dementia (AD). Monocytes, macrophages and microglia all express the marker colony-stimulating factor 1 receptor (CSF1R). 4-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(4-methylpiperidin-1-yl)phenyl)-1H-pyrrole-2-carboxamide (1) is a high-affinity antagonist for CSF1R. We report the radiosynthesis of both [3H]1 and [11C]1. The PET imaging properties of [11C]1 in mice and baboon were investigated. [3H]1 was studied in Bmax measurement in post-mortem autoradiography in the frontal cortex, inferior parietal cortex and hippocampus from donors diagnosed with AD and age-matched controls. In vitro binding affinity of 1 was measured commercially. Nor-methyl-1 precursor was radiolabeled with [11C]iodomethane or [3H]iodomethane to produce [11C]1 and [3H]1, respectively. Ex vivo brain biodistribution of [11C]1 was compared in normal mice versus lipopolysaccharide-administered (LPS) murine model of neuroinflammation. Dynamic PET imaging was performed in a healthy male Papio anubis baboon. Post-mortem autoradiography with [3H]1 was performed in frozen sections using a standard saturation binding technique.
RESULTS: Compound 1 exhibits a high in vitro CSF1R binding affinity (0.59 nM). [11C]1 was synthesized with high yield. [3H]1 was synthesized similarly (commercially). Biodistribution of [11C]1 in healthy mice demonstrated moderate brain uptake. In LPS-treated mice the brain uptake of [11C]1 was ~ 50% specific for CSF1R. PET/CT [11C]1 study in baboon revealed low brain uptake (0.36 SUV) of [11C]1. Autoradiography with [3H]1 gave significantly elevated Bmax values in AD frontal cortex versus control (47.78 ± 26.80 fmol/mg vs. 12.80 ± 5.30 fmol/mg, respectively, P = 0.023) and elevated, but not significantly different binding in AD hippocampus grey matter and inferior parietal cortex (IPC) white matter.
CONCLUSIONS: Compound 1 exhibits a high in vitro CSF1R binding affinity. [11C]1 specifically labels CSF1R in the mouse neuroinflammation, but lacks the ability to efficiently cross the blood-brain barrier in baboon PET. [3H]1 specifically labels CSF1R in post-mortem human brain. The binding of [3H]1 is significantly higher in the post-mortem frontal cortex of AD versus control subjects.

Keywords:  Alzheimer’s dementia; Bmax ; CD115; Colony stimulating factor 1 receptor; Inflammation imaging

DOI:  https://doi.org/10.1186/s13550-024-01133-2
Neurotrauma Rep. 2024 ;5(1): 770-786

Old Age Exacerbates White Matter Neuroinflammation and Cognitive Deficits Following Closed-Head Injury, Particularly in Female Mice.

Teresa Macheda, Margaret R Andres, Lydia Sanders, Kelly N Roberts, Ryan K Shahidehpour, Josh M Morganti, Adam D Bachstetter.

  The increasing incidence of traumatic brain injury (TBI) among older adults, particularly mild injuries from falls, underscores the need to investigate age-related outcomes and potential sex differences in response to TBI. Although previous research has defined an aging-TBI signature (heightened glial responses and cognitive impairment) in open-skull moderate-to-severe TBI models, it is unknown whether this signature is also present in mild closed-head injuries (CHIs). This study explores the influences of age and sex on recovery in a mouse CHI model induced by an electromagnetic impactor device in 4-month-old and 18-month-old C57BL/6 mice. We assessed the righting reflex, body weight, behavior (radial arm water maze and active avoidance), and inflammation (GFAP, IBA1, CD45) in the neocortex, corpus callosum, and hippocampus. We observed that aged female mice exhibited more severe TBI-induced cognitive deficits. In addition, a more pronounced reactive neuroinflammatory response with age was noted within white matter regions. Conversely, gray matter regions in aged animals either showed no enhanced pathological changes in response to injury or the aged mice displayed hyporesponsive glia and signs of dystrophic glial degeneration that were not evident in their younger counterparts following CHI. These findings suggest that aging influences CHI outcomes, partially reflecting the aging-TBI signature seen in more severe injuries in white matter, while a distinct aging and mild-TBI signature was identified in gray matter. The heightened vulnerability of females to the combined effects of age and mild CHI establishes a foundation for further investigation into the mechanisms underlying the sexually dimorphic response in aging females.

Keywords:  aging; astrocytes; brain injury; microglia; neuroinflammation; sex differences

DOI:  https://doi.org/10.1089/neur.2024.0074
Res Sq. 2024 Aug 12. pii: rs.3.rs-4782732. [Epub ahead of print]

Glial reactivity is linked to synaptic dysfunction across the aging and Alzheimer's disease spectrum.

Tharick Pascoal, Francieli Rohden, Pamela Ferreira, Bruna Bellaver, João Pedro Ferrari-Souza, Cristiano Aguzzoli, Carolina Soares, Sarah Abbas, Hussein Zalzale, Guilherme Povala, Firoza Lussier, Douglas Leffa, Guilherme Bauer-Negrini, Nesrine Rahmouni, Cécile Tissot, Joseph Therriault Therriault, Stijn Servaes, Jenna Stevenson, Andrea Benedet, Nicholas Ashton, Thomas Karikari, Dana Tudorascu, Henrik Zetterberg, Kaj Blennow, Eduardo Zimmer, Diogo Souza, Pedro Rosa-Neto.

Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease(AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available CSF measures of amyloid-β(Aβ), phosphorylated tau(pTau181), astrocyte reactivity(GFAP), microglial activation(sTREM2), and synaptic biomarkers(GAP43 and neurogranin). Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aβ presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aβ + individuals and postsynaptic biomarkers in cognitively impaired Aβ + individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.

DOI: https://doi.org/10.21203/rs.3.rs-4782732/v1
Neurosci Bull. 2024 Aug 27.

A Neuronal Activity-Boosting Microglial Function in Post-Anesthetic Emergence: How Microglial-Neuronal Crosstalk May Alter States of Consciousness.

Jared VanderZwaag, Marie-Ève Tremblay.

DOI: https://doi.org/10.1007/s12264-024-01256-5
Exp Gerontol. 2024 Aug 26. pii: S0531-5565(24)00204-3. [Epub ahead of print] 112558

Electroacupuncture regulates glucose metabolism by inhibiting SGLT1 levels, inhibiting microglial polarization, and alleviating Parkinson's disease.

Yanghong Zou, Tao Huang, Ailan Pang, Houjun Zhou, Xin Geng.

   BACKGROUND: Parkinson's disease (PD) is a common central neurodegenerative disease in middle-aged and elderly people. The progressive degeneration and death of dopaminergic neurons leads to insufficient dopamine (DA) neurotransmitters. Acupuncture and moxibustion can alleviate the aging of neurons. Therefore, studying the neuroprotective effects of electroacupuncture (EA) in PD mice is particularly important.
METHODS: Intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg) was used to establish a PD mouse model, and lipopolysaccharide (LPS) was used to induce microglia polarization. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Nissl staining and immunohistochemistry were used to detect neuronal apoptosis and injury, α-syn expression and microglial accumulation in PD mice. In addition, the levels of serum inflammatory factors were determined using enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect the Ca2+ content. The fluorescein isothiocyanate (FITC) labeling method was used to assess glucose uptake. A reagent kit was used to detect glucose and lactate levels.
RESULTS: MPTP induced the selective loss of DA neurons in the SN of mice, altered Ca2+ homeostasis, and induced an inflammatory response. In addition, maintaining Ca2+ homeostasis depends on the activity of transient receptor potential channel 1 (TRPC1). EA therapy promotes TRPC1 expression, which has a negative regulatory effect on sodium-glucose cotransporter 1 (SGLT1). Under the action of EA, TRPC1 protein expression increased, Ca2+ concentrations increased, and the effect of SGLT1 was inhibited, thereby facilitating glucose metabolism, blocking the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, restraining M1 polarization of microglia, and alleviating the PD process.
CONCLUSION: EA promotes TRPC1/Ca2+ pathway activation, inhibits SGLT1-mediated regulation of glucose metabolism and PI3K/AKT pathway activation, inhibits microglial M1 polarization, and alleviates PD.

Keywords:  Electroacupuncture; Glucose metabolism; Parkinson's disease; Polarization of microglia; SGLT1

DOI:  https://doi.org/10.1016/j.exger.2024.112558
Brain Behav Immun. 2024 Aug 24. pii: S0889-1591(24)00567-1. [Epub ahead of print]122 353-367

Effects of social dominance and acute social stress on morphology of microglia and structural integrity of the medial prefrontal cortex.

J Alex Grizzell, Thomas T Clarity, R Mason Rodriguez, Zachary Q Marshall, Matthew A Cooper.

  Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.

Keywords:  Aggression; Infralimbic cortex; Microglia; Minocycline; Resilience; Social defeat

DOI:  https://doi.org/10.1016/j.bbi.2024.08.043
Brain Behav Immun. 2024 Aug 25. pii: S0889-1591(24)00568-3. [Epub ahead of print]122 444-455

CD8+ T cells exacerbate AD-like symptoms in mouse model of amyloidosis.

Xin Wang, Britney Campbell, Monica Bodogai, Ross A McDevitt, Anton Patrikeev, Fedor Gusev, Emeline Ragonnaud, Konda Kumaraswami, Sophie Shirenova, Karin Vardy, Mohamed-Gabriel Alameh, Drew Weissman, Hellen Ishikawa-Ankerhold, Eitan Okun, Evgeny Rogaev, Arya Biragyn.

  Alzheimer's disease (AD) is linked to toxic Aβ plaques in the brain and activation of innate responses. Recent findings however suggest that the disease may also depend on the adaptive immunity, as B cells exacerbate and CD8+ T cells limit AD-like pathology in mouse models of amyloidosis. Here, by artificially blocking or augmenting CD8+ T cells in the brain of 5xFAD mice, we provide evidence that AD-like pathology is promoted by pathogenic, proinflammatory cytokines and exhaustion markers expressing CXCR6+ CD39+CD73+/- CD8+ TRM-like cells. The CD8+ T cells appear to act by targeting disease associated microglia (DAM), as we find them in tight complexes with microglia around Aβ plaques in the brain of mice and humans with AD. We also report that these CD8+ T cells are induced by B cells in the periphery, further underscoring the pathogenic importance of the adaptive immunity in AD. We propose that CD8+ T cells and B cells should be considered as therapeutic targets for control of AD, as their ablation at the onset of AD is sufficient to decrease CD8+ T cells in the brain and block the amyloidosis-linked neurodegeneration.

Keywords:  Alzheimer’s disease; Amyloidosis; Aβ response; B cells; CD8(+) T cells

DOI:  https://doi.org/10.1016/j.bbi.2024.08.045
Brain. 2024 Aug 28. pii: awae221. [Epub ahead of print]

Amyloid-β-activated microglia can induce compound proteinopathies.

Sang Hwan Lee, Eun-Jin Bae, Dayana Perez-Acuna, Min Kyo Jung, Jong Won Han, Inhee Mook-Jung, Seung-Jae Lee.

  Neuropathological features of Alzheimer's disease include amyloid plaques, neurofibrillary tangles and Lewy bodies, with the former preceding the latter two. However, it is not fully understood how these compound proteinopathies are interconnected. Here, we show that transplantation of amyloid-β oligomer-activated microglia into the striatum of naïve mice was sufficient to generate all the features of Alzheimer's disease, including widespread tauopathy and synucleinopathy, gliosis, neuroinflammation, synapse loss, neuronal death, and cognitive and motor deficits. These pathological features were eliminated by microglia depletion and anti-inflammatory drug administration. Our results suggest the crucial roles of microglia-driven inflammation in development of mixed pathology. This study provides not only mechanistic insights into amyloid-β oligomer-triggered proteinopathies but also a novel animal model recapitulating the salient features of Alzheimer's disease.

Keywords:  Alzheimer’s disease; microglia; neurodegeneration; neuroinflammation; tau; α-synuclein

DOI:  https://doi.org/10.1093/brain/awae221
Mol Biol Rep. 2024 Aug 28. 51(1): 941

Exosomal miRNA-21 derived from umbilical cord mesenchymal stem cells inhibits microglial overactivation to counteract nerve damage.

Lianxu Cui, Dongsheng Li, Junrong Xu, Haomin Li, Yufeng Pan, Jianguo Qiu, Siwei Peng, You Wang, Chen Wang, Jinhui Wang, Guoqiang Chen.

   BACKGROUND: Traumatic brain injury (TBI) is a major cause of neurological disability, and current treatments have limited effectiveness. Recent studies have emphasized the potential of exosomes derived from umbilical cord mesenchymal stem cells (UC-MSCs-Exo) in TBI treatment, but the molecular mechanisms underlying their therapeutic effects are not fully understood.
METHODS AND RESULTS: In this study, UC-MSCs-Exo was isolated using ultracentrifugation and intraventricularly injected to TBI rat model. The neurofunctional motor function of the rats was evaluated using the modified neurological severity score (mNSS), and the activation of microglia was assessed through immunofluorescence detection of IBA1 expression levels. Additionally, we established an in vitro neuroinflammatory model using BV2 microglia to investigate the effects of UC-MSCs-Exo and miRNA-21. Our findings indicate that UC-MSCs-Exo promote neurological recovery in TBI rats and inhibit excessive microglia activation. Furthermore, UC-MSCs-Exo highly expresses miRNA-21 and inhibited the proliferation, migration, and release of inflammatory mediators of BV2 microglia by transporting miRNA-21.
CONCLUSIONS: The present study suggests that the promotion of neurological recovery in TBI rats by UC-MSCs-Exo may be attributed to the inhibition of excessive microglia activation through miRNA-21.

Keywords:  Mesenchymal stem cell exosomes; Microglia; Nerve damage; Traumatic brain injury; miRNA

DOI:  https://doi.org/10.1007/s11033-024-09878-8
Biomolecules. 2024 Aug 08. pii: 964. [Epub ahead of print]14(8):

Microglia: The Drunken Gardeners of Early Adversity.

Sahabuddin Ahmed, Baruh Polis, Arie Kaffman.

  Early life adversity (ELA) is a heterogeneous group of negative childhood experiences that can lead to abnormal brain development and more severe psychiatric, neurological, and medical conditions in adulthood. According to the immune hypothesis, ELA leads to an abnormal immune response characterized by high levels of inflammatory cytokines. This abnormal immune response contributes to more severe negative health outcomes and a refractory response to treatment in individuals with a history of ELA. Here, we examine this hypothesis in the context of recent rodent studies that focus on the impact of ELA on microglia, the resident immune cells in the brain. We review recent progress in our ability to mechanistically link molecular alterations in microglial function during a critical period of development with changes in synaptic connectivity, cognition, and stress reactivity later in life. We also examine recent research showing that ELA induces long-term alterations in microglial inflammatory response to "secondary hits" such as traumatic brain injury, substance use, and exposure to additional stress in adulthood. We conclude with a discussion on future directions and unresolved questions regarding the signals that modify microglial function and the clinical significance of rodent studies for humans.

Keywords:  early adversity; limited bedding and nesting; maternal separation; microglia; neurodevelopment; synaptic pruning

DOI:  https://doi.org/10.3390/biom14080964
Int J Mol Sci. 2024 Aug 13. pii: 8784. [Epub ahead of print]25(16):

Increased Pan-Type, A1-Type, and A2-Type Astrocyte Activation and Upstream Inflammatory Markers Are Induced by the P2X7 Receptor.

Keith E Campagno, Puttipong Sripinun, Lily P See, Jiaqi Li, Wennan Lu, Assraa Hassan Jassim, Néstor Más Gómez, Claire H Mitchell.

  This study asked whether the P2X7 receptor was necessary and sufficient to trigger astrocyte polarization into neuroinflammatory activation states. Intravitreal injection of agonist BzATP increased gene expression of pan-astrocyte activation markers Gfap, Steap4, and Vim and A1-type astrocyte activation markers C3, Serping1, and H2T23, but also the Cd14 and Ptx3 genes usually associated with the A2-type astrocyte activation state and Tnfa, IL1a, and C1qa, assumed to be upstream of astrocyte activation in microglia. Correlation analysis of gene expression suggested the P2X7 receptor induced a mixed A1/A2-astrocyte activation state, although A1-state genes like C3 increased the most. A similar pattern of mixed glial activation genes occurred one day after intraocular pressure (IOP) was elevated in wild-type mice, but not in P2X7-/- mice, suggesting the P2X7 receptor is necessary for the glial activation that accompanies IOP elevation. In summary, this study suggests stimulation of the P2X7R is necessary and sufficient to trigger the astrocyte activation in the retina following IOP elevation, with a rise in markers for pan-, A1-, and A2-type astrocyte activation. The P2X7 receptor is expressed on microglia, optic nerve head astrocytes, and retinal ganglion cells (RGCs) in the retina, and can be stimulated by the mechanosensitive release of ATP that accompanies IOP elevation. Whether the P2X7 receptor connects this mechanosensitive ATP release to microglial and astrocyte polarization in glaucoma remains to be determined.

Keywords:  C3; P2X7; glaucoma; microglia; neuroinflammation; neurotoxic astrocyte polarization; retinal ganglion cells

DOI:  https://doi.org/10.3390/ijms25168784
Inflammation. 2024 Aug 27.

The Immunomodulatory Effect of Silver Nanoparticles in a Retinal Inflammatory Environment.

Katerina Palacka, Barbora Hermankova, Tereza Cervena, Pavel Rossner, Alena Zajicova, Eva Uherkova, Vladimir Holan, Eliska Javorkova.

  Activation of immune response plays an important role in the development of retinal diseases. One of the main populations of immune cells contributing to the retinal homeostasis are microglia, which represent a population of residential macrophages. However, under pathological conditions, microglia become activated and rather support a harmful inflammatory reaction and retinal angiogenesis. Therefore, targeting these cells could provide protection against retinal neuroinflammation and neovascularization. In the recent study, we analyzed effects of silver nanoparticles (AgNPs) on microglia in vitro and in vivo. We showed that the AgNPs interact in vitro with stimulated mouse CD45/CD11b positive cells (microglia/macrophages), decrease their secretion of nitric oxide and vascular endothelial growth factor, and regulate the expression of genes for Iba-1 and interleukin-1β (IL-1β). In our in vivo experimental mouse model, the intravitreal application of a mixture of proinflammatory cytokines tumor necrosis factor-α, IL-1β and interferon-γ induced local inflammation and increased local expression of genes for inducible nitric oxide synthase, IL-α, IL-1β and galectin-3 in the retina. This stimulation of local inflammatory reaction was significantly inhibited by intravitreal administration of AgNPs. The application of AgNPs also decreased the presence of CD11b/Galectin-3 positive cells in neuroinflammatory retina, but did not influence viability of cells and expression of gene for rhodopsin in the retinal tissue. These data indicate that AgNPs regulate reactivity of activated microglia in the diseased retina and thus could provide a beneficial effect for the treatment of several retinal diseases.

Keywords:  Microglia; Neovascularization; Neuroinflammation; Retinal diseases; Silver nanoparticles

DOI:  https://doi.org/10.1007/s10753-024-02128-w
J Neuroimmune Pharmacol. 2024 Aug 28. 19(1): 48

Tetramerization of PKM2 Alleviates Traumatic Brain Injury by Ameliorating Mitochondrial Damage in Microglia.

Haiyan Zhu, Huiwen Zhang, Xiao-Jing Zhao, Lingyuan Zhang, Xue Liu, Zhi-Yuan Zhang, Yi-Zhi Ren, Yong Feng.

  Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events that determine the outcome of TBI, especially neuronal and cognitive function. Studies have suggested that the metabolic characteristics of microglia dictate their inflammatory response. The pyruvate kinase isoform M2 (PKM2), a key glycolytic enzyme, is involved in the regulation of various cellular metabolic processes, including mitochondrial metabolism. This suggests that PKM2 may also participate in the regulation of microglial activation during TBI. Therefore, the present study aimed to evaluate the role of PKM2 in regulating microglial activation and neuroinflammation and its effects on cognitive function following TBI. A controlled cortical impact (CCI) mouse model and inflammation-induced primary mouse microglial cells in vitro were used to investigate the potential effects of PKM2 inhibition and regulation. PKM2 was significantly increased during the acute and subacute phases of TBI and was predominantly detected in microglia rather than in neurons. Our results demonstrate that shikonin and TEPP-46 can inhibit microglial inflammation, improving mitochondria, improving mouse behavior, reducing brain defect volume, and alleviating pathological changes after TBI. There is a difference in the intervention of shikonin and TEPP-46 on PKM2. Shikonin directly inhibits General PKM2; TEPP-46 can promote the expression of PKM2 tetramer. In vitro experiments, TEPP-46 can promote the expression of PKM2 tetramer, enhance the interaction between PKM2 and MFN2, improve mitochondria, alleviate neuroinflammation. General inhibition and tetramerization activation of PKM2 attenuated cognitive function caused by TBI, whereas PKM2 tetramerization exhibited a better treatment effect. Our experiments demonstrated the non-metabolic role of PKM2 in the regulation of microglial activation following TBI. Both shikonin and TEPP-46 can inhibit pro-inflammatory factors, but only TEPP-46 can promote PKM2 tetramerization and upregulate the release of anti-inflammatory factors from microglia.

Keywords:  MFN2; Microglia; Mitochondria; PKM2; TBI

DOI:  https://doi.org/10.1007/s11481-024-10138-6
bioRxiv. 2024 Aug 12. pii: 2024.08.12.607566. [Epub ahead of print]

Microglia are Required for Developmental Specification of AgRP Innervation in the Hypothalamus of Offspring Exposed to Maternal High Fat Diet During Lactation.

Haley N Mendoza-Romero, Jessica E Biddinger, Michelle N Bedenbaugh, Richard B Simerly.

  Nutritional fluctuations that occur early in life dictate metabolic adaptations that will affect susceptibility to weight gain and obesity later in life. The postnatal period in mice represents a time of dynamic changes in hypothalamic development and maternal consumption of a high fat diet during the lactation period (MHFD) changes the composition of milk and leads to enhanced susceptibility to obesity in offspring. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) react to changes in multiple metabolic signals and distribute neuroendocrine information to other brain regions, such as the paraventricular hypothalamic nucleus (PVH), which is known to integrate a variety of signals that regulate body weight. Development of neural projections from AgRP neurons to the PVH occurs during the lactation period and these projections are reduced in MHFD offspring, but underlying developmental mechanisms remain largely unknown. Microglia are the resident immune cells of the central nervous system and are involved in refinement of neural connections and modulation of synaptic transmission. Because high fat diet exposure causes activation of microglia in adults, a similar activation may occur in offspring exposed to MHFD and play a role in sculpting hypothalamic feeding circuitry. Genetically targeted axonal labeling and immunohistochemistry were used to visualize AgRP axons and microglia in postnatal mice derived from MHFD dams and morphological changes quantified. The results demonstrate regionally localized changes to microglial morphology in the PVH of MHFD offspring that suggest enhanced surveillance activity and are temporally restricted to the period when AgRP neurons innervate the PVH. In addition, axon labeling experiments confirm a significant decrease in AgRP innervation of the PVH in MHFD offspring and provide direct evidence of synaptic pruning of AgRP inputs to the PVH. Microglial depletion with the Colony-stimulating factor 1 receptor inhibitor PLX5622 determined that the decrease in AgRP innervation observed in MHFD offspring is dependent on microglia, and that microglia are required for weight gain that emerges as early as weaning in offspring of MHFD dams. However, these changes do not appear to be dependent on the degree of microglial mediated synaptic pruning. Together, these findings suggest that microglia are activated by exposure to MHFD and interact directly with AgRP axons during development to permanently alter their density, with implications for developmental programming of metabolic phenotype.

Keywords:  Agouti-related peptide; Developmental Biology; Hypothalamus; Major category; Microglia; Minor category; Neural Development; Neuroscience; Paraventricular hypothalamic nucleus

DOI:  https://doi.org/10.1101/2024.08.12.607566
Eur J Neurosci. 2024 Aug 26.

Trazodone counteracts the response of microglial cells to inflammatory stimuli.

Elisa Chelucci, Simona Daniele, Matteo Vergassola, Lorenzo Ceccarelli, Sara Zucchi, Luigi Boltri, Claudia Martini.

  Microglia are resident brain cells that regulate neuronal development and innate immunity. Microglia activation participates in the cellular response to neuroinflammation, thus representing a possible target for pharmacological strategies aimed to counteract the onset and progression of brain disorders, including depression. Antidepressant drugs have been reported to reduce neuroinflammation by acting also on glial cells. Herein, the potential anti-inflammatory and neuroprotective effects of trazodone (TRZ) on the microglial human microglial clone 3 (HMC3) cell line were investigated. HMC3 cells were activated by a double inflammatory stimulus (lipopolysaccharide [LPS] and tumour necrosis factor-alpha [TNF-α], 24 h each), and the induction of inflammation was demonstrated by (i) the increased expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and ionized calcium-binding adapter molecule 1 (IBA-1), and (ii) the increased release of interleukin 6 (IL-6) and transforming growth factor-beta (TGF-β). TRZ effects were evaluated by treating HMC3 cells for 24 h before (pre-treatment) and after (post-treatment) the double inflammatory stimulus. Notably, TRZ treatments significantly decreased the expression of NF-kB and IBA-1 and the release of the cytokines IL-6 and TGF-β. Moreover, TRZ prevented and reduced the release of quinolinic acid (QUIN), a known neurotoxic kynurenine metabolite. Finally, cellular supernatants collected from microglial cells pre-treated LPS-TNF-α with TRZ were able to improve neuronal-like cell viability, demonstrating a potential neuroprotective effect. Overall, this study suggests the anti-inflammatory effects of TRZ on human microglia and strives for its neuroprotective properties.

Keywords:  antidepressant drug; microglia; neuroinflammation; neuroprotection; trazodone

DOI:  https://doi.org/10.1111/ejn.16522
iScience. 2024 Aug 16. 27(8): 110546

Purinergic exposure induces epigenomic and transcriptomic-mediated preconditioning resembling epilepsy-associated microglial states.

Ricardo Martins-Ferreira, Josep Calafell-Segura, João Chaves, Laura Ciudad, António Martins da Silva, Paulo Pinho E Costa, Bárbara Leal, Esteban Ballestar.

  Microglia play a crucial role in a range of neuropathologies through exacerbated activation. Microglial inflammatory responses can be influenced by prior exposures to noxious stimuli, like increased levels of extracellular adenosine and ATP. These are characteristic of brain insults like epileptic seizures and could potentially shape subsequent responses through epigenetic regulation. We investigated DNA methylation and expression changes in human microglia-like cells differentiated from monocytes following ATP-mediated preconditioning. We demonstrate that microglia-like cells display homeostatic microglial features, shown by surface markers, transcriptome, and DNA methylome. After exposure to ATP, TLR-mediated activation leads to an exacerbated pro-inflammatory response. These changes are accompanied by methylation and transcriptional reprogramming associated with enhanced immune-related functions. The reprogramming associated with ATP-mediated preconditioning leads to profiles found in microglial subsets linked to epilepsy. Purine-driven microglia immune preconditioning drives epigenetic and transcriptional changes that could contribute to altered functions of microglia during seizure development and progression.

Keywords:  Epigenetics; Epilepsy; Microglia; Purines; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.110546