Glia最新文献

{"title":"Microglial P2ry12 in the Basolateral Amygdala Underlies Neuropathic Pain-Induced Anxiety","authors":"Xiaohui Yang,&nbsp;Li Chen,&nbsp;Qiuxiao Shi,&nbsp;Hanmin Liu,&nbsp;Yuying Tang","doi":"10.1002/glia.70196","DOIUrl":"10.1002/glia.70196","url":null,"abstract":"<div>\u0000 \u0000 <p>Anxiety is a common clinical comorbidity of neuropathic pain. The basolateral amygdala (BLA) is critically involved in both pain and anxiety processing. Microglia have emerged as key regulators of neuronal plasticity, and disruption of homeostatic neuron–microglia crosstalk can precipitate neuropsychiatric disorders. Although microglia are abundant in the BLA, their specific role in modulating neuronal plasticity underlying pain-induced anxiety remains poorly understood. Here, we demonstrate that spared nerve injury (SNI) induces anxiety-like behaviors in mice, accompanied by neuronal hyperexcitability and increased spine density in the BLA. These changes correlated with increased density of hyper-ramified microglia, along with upregulated P2ry12 expression and enhanced microglial BDNF production. Importantly, microglial P2ry12 knockdown significantly attenuated both process hyper-ramification and BDNF overexpression in the BLA. Furthermore, either microglial depletion with clodronate or microglial P2ry12 knockdown in the BLA reversed neuronal hyperexcitability and spine overgrowth, and alleviated pain and anxiety-like behaviors in SNI mice. Meanwhile, clodronate mildly suppressed neuronal excitability and dendritic spine density in the BLA of control mice, whereas P2ry12 knockdown had no detectable impact on these neuronal measures. Together, these findings support a role for microglia in maintaining physiological neuronal excitability and spine density. Highly-ramified microglia and their increased P2ry12 expression underlie the enhanced neuronal excitability and spine density in the BLA, thereby promoting comorbidity of pain and anxiety.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the Functional Role of KIF21B in Microglia Inflammatory Response","authors":"Danny Ganchala,&nbsp;Alvaro Bautista-Abad,&nbsp;Daniel Pinto-Benito,&nbsp;Julia Simon-Areces,&nbsp;Daniela Grassi,&nbsp;Francesco Paolo Ulloa Severino,&nbsp;Maria-Angeles Arevalo","doi":"10.1002/glia.70198","DOIUrl":"10.1002/glia.70198","url":null,"abstract":"<p>Microglia are brain immune cells that maintain homeostasis and respond to injury, changing cell morphology to drive inflammation, migration, and phagocytosis. This study examined the role of the kinesin KIF21B in microglial activation, demonstrating for the first time its expression in microglial cells in two in vivo neuroinflammatory models: TBI (focal inflammation) and LPS administration (diffuse inflammation). While TBI provoked a significant increase in KIF21B/Iba1 colocalization in the tissue around the lesion exclusively in females, LPS administration did not alter KIF21B expression in either sex. Given the importance of cytoskeleton remodeling for microglial migration and phagocytosis, this work investigates whether KIF21B contributes to these actions. Downregulating KIF21B in primary cultured mouse microglia had sex-specific effects. In females, KIF21B silencing reduced both migratory capacity and phagocytosis of <i>E. coli</i>-coated spheres and neuronal debris. In males, it exacerbated migration and selectively increased neuronal debris phagocytosis, while <i>E. coli</i>-coated sphere uptake remained unaffected. These functional differences were accompanied by sex-dependent morphological alterations, quantified through area, circularity, Feret's diameter, and perimeter: KIF21B silencing blocked the transition to amoeboid morphology in females while inducing hyperpolarized elongation in males. Finally, LPS treatment increased KIF21B colocalization with microtubules and reduced its colocalization with F-actin in females, while neither interaction was significantly altered in males. Overall, the findings suggest that KIF21B regulates microglial function in a sex-dependent manner through its effects on cytoskeletal organization.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dorso-Ventral and Night-Day Regulation of Extracellular K+ Dynamics in Mouse Hippocampal Astrocytes","authors":"Nariman Kiani,&nbsp;Kabeer Abubakar,&nbsp;Tin Luka Petanjek,&nbsp;Monique Esclapez,&nbsp;Anton Ivanov,&nbsp;Christophe Bernard","doi":"10.1002/glia.70201","DOIUrl":"10.1002/glia.70201","url":null,"abstract":"<p>Astrocytes regulate extracellular potassium (K⁺) through multiple mechanisms operating across distinct spatiotemporal scales, yet whether this regulation exhibits regional and circadian specificity remains unclear. Using real-time K⁺ measurements combined with electrophysiology and immunohistochemistry in astrocytes, we characterize K⁺ buffering by astrocytes across the dorsoventral hippocampal axis at three circadian times. We report that hippocampal CA1 <i>stratum radiatum</i> astrocytes possess different functional K⁺ buffering capacities depending on both anatomical location and time of day. At the early light phase (ZT3), the ventral hippocampus (VH) exhibits faster K⁺ accumulation and greater peak amplitudes than the dorsal hippocampus (DH) in response to similar neuronal network activity. This regional divergence is driven by reduced Kir4.1 channel function in VH astrocytes, which persists across all measured time points, and which is partially compensated by enhanced Na⁺/K⁺-ATPase activity specifically at ZT3. Gap junction coupling between astrocytes shows regional and time-dependent variation, with elevated coupling in VH at ZT3 that subsequently normalizes. Kir4.1 protein expression exhibits circadian dynamics. In contrast to the steady, high levels of Kir4.1 observed in the DH, the VH shows a gradual increase in expression across the light–dark cycle. These findings establish astrocytic K⁺ buffering as a multiscale phenomenon integrating regional heterogeneity with circadian regulation, with implications for understanding regional and temporal differences in network excitability, particularly in epilepsy.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPR17+ Oligodendrocyte Lineage Cells Regulate the Critical Period of Brain Development Through Novel Chondroitin Sulfate-Rich Structures","authors":"Takahiro Tanaka,&nbsp;Aurelien Kerever,&nbsp;Yuji Suzuki,&nbsp;Taro Kunitomi,&nbsp;Kana Kato,&nbsp;Yuri Yamashita,&nbsp;Kyohei Higashi,&nbsp;Chihiro Akazawa,&nbsp;Fumihito Saitow,&nbsp;Hidenori Suzuki,&nbsp;Eri Arikawa-Hirasawa","doi":"10.1002/glia.70188","DOIUrl":"10.1002/glia.70188","url":null,"abstract":"<div>\u0000 \u0000 <p>The extracellular matrix (ECM) of the brain undergoes dynamic remodeling during development and is crucial for neuronal plasticity. While chondroitin sulfates (CS) regulate oligodendrocyte differentiation and myelination, their relationship with oligodendrocyte precursors (OPCs) and synaptic plasticity remains unclear. This study investigated a novel CS-rich ECM structure, its origin, and its role in synaptic plasticity. Using immunohistochemistry, disaccharide analysis, and dendritic spine characterization in mice, we examined postnatal development and analyzed single-cell RNA (scRNA) sequencing data from the National Center for Biotechnology Information database. We identified patch-like structures labeled with the chondroitin sulfate 56 (CS56) antibody (CS clusters) distinct from <i>Wisteria floribunda</i> agglutinin-positive perineuronal nets. Oligodendrocyte lineage cells expressing G protein-coupled receptor 17 (GPR17) localized at CS cluster centers, emerging postnatally and peaking at day 14, preceded CS cluster formation. ScRNA sequencing of <i>Gpr17</i>+ cells revealed the expression of carbohydrate sulfotransferase 3 (<i>Chst3</i>) and uronyl 2-sulfotransferase (<i>Ust</i>), genes coding enzymes synthesizing type C and D CS disaccharides, the primary components of the CS56 antibody epitope. Disaccharide analysis revealed elevated levels of type D chondroitin sulfate at day 35. Notably, dendritic spines within the CS clusters were longer and larger than those outside these regions, suggesting enhanced synaptic connectivity. Our findings reveal a CS-rich structure in the brain ECM that is causally linked to GPR17+ oligodendrocyte lineage cells and closely related to neuronal circuit development. The morphological differences in dendritic spines within CS clusters and persistence of GPR17+ oligodendrocyte lineage cells beyond the postnatal period suggest additional functions that warrant further investigation.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Super-Resolution Approach for Astrocyte-Specific Molecular Imaging Reveals the Nanoscale Distribution of Monoacylglycerol Lipase, the Metabolic Node Between Endocannabinoid and Prostaglandin Signaling","authors":"Miklós Zöldi,&nbsp;István Katona","doi":"10.1002/glia.70186","DOIUrl":"10.1002/glia.70186","url":null,"abstract":"<p>Astrocytes play essential roles in brain function and disorders. Yet, compared to neurons, our knowledge of the physiological and pathological signaling mechanisms in astrocytes remains limited. As a major challenge, the ultrathin (~10–100 nm) processes of astrocytes render high-throughput quantitative molecular imaging within well-defined cellular contexts very difficult. Here, we introduce a single-molecule localization microscopy-based methodology that achieves unprecedented resolution of the intricate astrocytic arbor in intact brain circuits. Postnatal tagging of the plasma membrane by electroporation in mice resulted in selective and sparse labeling of hippocampal astrocytes and enabled the complete visualization of individual astrocytes with nanoscale precision by using STochastic Optical Reconstruction Microscopy (STORM). We also developed high-yield and easy-to-implement approaches to segment, measure, analyze, and visualize nanoscale molecular information within astrocytic compartments. As a proof-of-concept, we could readily differentiate between synaptic and astrocytic proteins by using dual-color STORM super-resolution imaging. Moreover, we identified cell-type-specific differences in the distribution of monoacylglycerol lipase (MAGL), an enzyme regulating synaptic plasticity in neurons and coupling endocannabinoid signaling to prostaglandin signaling in astrocytes. Our findings demonstrate the feasibility of nanoscale molecular measurements within ultrathin astrocytic processes. Moreover, the results provide insights into the synapse-independent nanoscale arrangement of the astrocytic MAGL pool that controls neuroinflammatory processes.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148373960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking CK2α-Bclaf1 Preserves Oligodendrocytes After Neonatal Hypoxic Injury","authors":"Chien-Fang Huang,&nbsp;Ti-Jie Yuan,&nbsp;Ming-Yi Lin,&nbsp;Yuan-Ting Sun,&nbsp;Chih-Yen Wang","doi":"10.1002/glia.70187","DOIUrl":"https://doi.org/10.1002/glia.70187","url":null,"abstract":"<div>\u0000 \u0000 <p>Neonatal hypoxic injury is a common disorder that disrupts white matter development in preterm newborns, with long-term impacts on cognitive and mental function. While oxygen availability controls oligodendrocyte (OL) differentiation, prolonged hypoxia leads to OL death and impairs subsequent myelination even after returning to normoxic conditions. In this study, we uncovered the detrimental roles of the serine/threonine kinase CK2α and the transcriptional factor Bclaf1 in OL survival under hypoxic conditions. Phosphorylated Bclaf1 by CK2α drives hypoxia-mediated OL apoptosis, which can be reversed by introducing the hypoxia-inducible E3 ligase Vhl. Additionally, acute treatment with the clinically approved CK2 inhibitor silmitasertib and the herbal supplement curcumin not only reduces CK2α-Bclaf1 activity but also protects OLs and restores pre-myelinating ability in newborns following hypoxic injury. This approach unveils a key molecular regulation in hypoxia-related OL pathology and highlights a potential therapeutic strategy to mitigate neonatal hypoxic injury and prevent mental health complications.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial Pruning of Excitatory Synapses in the Hippocampus Is Complement C3-Independent in Physiological and Neuroinflammatory States.","authors":"Eric W Salter, Ashish Kadia, Lijia Zhang, Jonathan S Thacker, Sun-Lim Choi, Liam T Ralph, Gang Lei, Fuzi Jin, John Georgiou, Graham L Collingridge","doi":"10.1002/glia.70154","DOIUrl":"10.1002/glia.70154","url":null,"abstract":"<p><p>A key feature of brain development is the refinement of exuberant synapses, known as synapse pruning. This phenomenon is executed by microglia, the resident immune cells of the brain. Evidence that microglia prune retinal inputs via activation of the complement cascade in the dorsolateral geniculate nucleus (dLGN) has led to the widely held view that complement-dependent synapse pruning occurs ubiquitously in the brain. However, evidence for developmental complement-dependent pruning in regions outside of the dLGN is largely absent. Here, we tested for complement-dependent synapse pruning by microglia in the hippocampus, a central region for learning and memory. We hypothesized that complement-dependent pruning by microglia occurs at VGLUT2⁺ synapses, where complement proteins are enriched in the hippocampus. We analyzed mice genetically lacking the central complement component C3 (C3^-/-) that have broad inhibition of complement cascade activity. We found that microglia-mediated VGLUT2 engulfment was not significantly impaired in C3^-/- compared to wildtype (WT) mice in the hippocampus in both late postnatal development and early adulthood. Further, functional synapse properties were not significantly altered in C3^-/- compared to WT mice. Finally, we tested whether a complement-dependent pruning mechanism could be induced in the hippocampus via peripheral inflammation. Lipopolysaccharide (LPS) injections induced a neuroinflammatory phenotype associated with loss of VGLUT2⁺ synapses. However, in an LPS-induced neuroinflammatory state, VGLUT2⁺ synapse pruning by microglia was not affected in C3^-/- mice. These findings uncover that C3 is not ubiquitously required for synapse engulfment in physiological and neuroinflammatory conditions in the hippocampus.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 7","pages":"e70154"},"PeriodicalIF":5.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced SH3RF3 May Protect Against Alzheimer's Disease by Lowering Microglial Pro-Inflammatory Responses via Modulation of JNK and NFkB Signaling.","authors":"Ronak Patel, Rong Cheng, Christopher L Cardona, Ellen Angeles, Gunjandeep Singh, Sabrina Miller, Archana Ashok, Andrew F Teich, Angel Piriz, Aleyda Maldonado, Ivonne Z Jiménez-Velázquez, Richard Mayeux, Joseph H Lee, Andrew A Sproul","doi":"10.1002/glia.70165","DOIUrl":"10.1002/glia.70165","url":null,"abstract":"<p><p>Understanding how high-risk individuals are protected from Alzheimer's disease (AD) may illuminate potential therapeutic targets. We identified protective genetic variants in SH3RF3/POSH2 that delayed the onset of AD among individuals carrying the PSEN1^G206A mutation. SH3RF3 acts as a JNK pathway scaffold and activates NFκB signaling. While the effects of SH3RF3 knockdown in human neurons were subtle, including decreased pTau S422, knockdown in human microglia significantly reduced inflammatory cytokines in response to either a viral mimic or oAβ42. This was associated with reduced activation of JNK and NFκB pathways in response to these stimuli. Pharmacological inhibition of JNK or NFκB signaling phenocopied SH3RF3 knockdown. We also found PSEN1^G206A microglia had a reduced inflammatory response to oAβ42. Thus, further reduction of microglial inflammatory responses in PSEN1^G206A mutant carriers by protective variants in SH3RF3 might reduce the link between amyloid and neuroinflammation to subsequently delay the onset of AD.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 7","pages":"e70165"},"PeriodicalIF":5.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Characteristics and Differentiation Control Mechanisms of Bergmann Glia-Like Progenitors in the Postnatal Mouse Cerebellum","authors":"Kyoka Suyama,&nbsp;Toma Adachi,&nbsp;Minami Mizuno,&nbsp;Kaiyuan Ji,&nbsp;Eriko Isogai,&nbsp;Ikuko Hasegawa,&nbsp;Kayo Nishitani,&nbsp;Masaki Sone,&nbsp;Satoshi Miyashita,&nbsp;Tomoo Owa,&nbsp;Mikio Hoshino","doi":"10.1002/glia.70160","DOIUrl":"https://doi.org/10.1002/glia.70160","url":null,"abstract":"<div>\u0000 \u0000 <p>In the mammalian cerebellum, three types of astroglial cells—Bergmann glial cells (BGs), inner granule cell layer (IGL) astrocytes, and white matter (WM) astrocytes—arise in postnatal timing from two types of progenitors: Bergmann glia-like progenitors (BGLPs) and astrocyte-like progenitors (AsLPs). In contrast to AsLPs, which are commonly observed in other brain regions, BGLPs have not been well studied. Here, we investigate differentiation abilities, gene expression profiles and differentiation control mechanisms of BGLPs at postnatal stages. BGLPs and AsLPs decrease in number as development progresses from postnatal day 0 (P0), and are almost absent by P10. By utilizing an electroporation-based method to BGLPs, we found that P6 BGLPs differentiate into BGs and IGL astrocytes, but not into WM astrocytes, consistent with a previous report. However, P0 BGLPs were observed to differentiate into not only BGs and IGL astrocytes, but also WM astrocytes and a small number of molecular layer inhibitory neurons. By conducting spatial transcriptomic analysis with over 5000 probes (Xenium), we successfully identified distinct clusters corresponding to BGLPs at P0 and P6, respectively, and genes preferentially expressed in P0 and P6 BGLPs. In addition, upstream regulatory analysis using Enrichr identified <i>Foxm1</i> and <i>Nfia</i> as candidate regulators that affect stage-specific properties of BGLPs. in vivo knockdown and overexpression experiments further demonstrated that precise regulation of <i>Foxm1</i> and <i>Nfia</i> expression is important for proper progeny production from postnatal BGLPs. This study gives insights into understanding molecular nature and differentiation ability control of BGLPs during postnatal cerebellar development.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Membrane Remodeling During Microglial Activation: A Hypothesis Linking Microglial Shape and Lipid Droplet Formation","authors":"G. William Rebeck,&nbsp;Giorgi Shautidze,&nbsp;Jordy Sepulveda,&nbsp;Gracie S. Healey,&nbsp;Priyanka S. Narayan","doi":"10.1002/glia.70193","DOIUrl":"10.1002/glia.70193","url":null,"abstract":"<p>Microglia are dynamic cells that respond both transcriptionally and morphologically to acute brain injury as well as to chronic neurodegenerative conditions. Upon activation, they become less ramified, more rounded, and accumulate intracellular lipid droplets. In this hypothesis paper, we propose that the formation of these lipid droplets supports the redistribution of plasma membrane lipids required during morphological remodeling. We rely on original and published studies of microglial morphology under conditions of aging, acute activation, and chronic activation. In ex vivo brain slices, microglia responded to either ATP or acute Aβ injections within minutes by extending their proximal processes toward the stimulus while simultaneously retracting their distal processes into their cell bodies. Chronic exposure to Aβ in mouse models of amyloid reduced microglial branching alongside a two- to three-fold loss of surface area. Transcriptomic analyses showed that activated microglia upregulate genes involved in fatty acid synthesis and fatty acid activation, both processes that are necessary in the production of triacylglycerol. Integrating these new and published analyses of microglia, we developed a hypothesis in which plasma membrane phospholipids are redistributed during acute activation and, during chronic activation, they are metabolized to triacylglycerol into lipid droplets. Tests of this hypothesis, through various pharmacological and genetic approaches, would contribute to our understanding of lipid droplets in cells that undergo substantial morphological changes.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148314912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}