bims-micgli Biomed News
on Microglia
Issue of 2025–09–14
eleven papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer's disease mouse model.
  2. Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity.
  3. The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids.
  4. 14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.
  5. Contrasting contribution of resident and repopulated brain macrophages in sustaining sleep-wake circuitry.
  6. Early microglia progenitors colonize the embryonic CNS via integrin-mediated migration from the pial surface.
  7. Metabolic dysregulation in Alzheimer's disease: A brain metabolomics approach.
  8. Neuroinflammation and Alzheimer's disease: Unravelling the molecular mechanisms.
  9. Microglia contribute to bipolar depression through Serinc2-dependent phospholipid synthesis.
  10. Human myelinated brain organoids with integrated microglia as a model for myelin repair and remyelinating therapies.
  11. Coordination of autophagosome closure and release by the Alzheimer's disease-associated protein BIN1.
  1. Acta Neuropathol Commun. 2025 Sep 10. 13(1): 190
    Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer's disease mouse model.
    David Ramonet, Anna Daerr, Martin Hallbeck.
      Disruptions in synaptic transmission and plasticity are early hallmarks of Alzheimer's disease (AD). Endosomal trafficking, mediated by the retromer complex, is essential for intracellular protein sorting, including the regulation of amyloid precursor protein (APP) processing. The VPS35 subunit, a key cargo-recognition component of the retromer, has been implicated in neurodegenerative diseases, with mutations such as L625P linked to early-onset AD. Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood. Here, we investigate the acute molecular effects of retromer stabilization in the 5xFAD mouse model of AD using the pharmacological chaperones R55 and R33, previously identified to enhance VPS35 stability. Following intracranial stereotaxic injections, we performed transcriptomic profiling, quantitative histology, and immunohistochemistry to assess synaptic function, neuroinflammation, and endosomal trafficking. Our findings reveal that retromer stabilization reverses multiple AD-associated molecular changes. R55 treatment significantly reduced Aβ-related pathology, normalized synaptic gene expression, and restored long-term potentiation (LTP)-associated pathways, including Gria1 (AMPA receptors), Grip1, and semaphorin/plexin signaling. Additionally, retromer stabilization counteracted dysregulated calcium signaling by modulating Ryr2 and L-type calcium channel expression. Beyond synaptic effects, we observed broad transcriptional and structural changes in the endosomal system. Notably, R55 treatment decreased VPS13 family gene expression, implicated in membrane contact site regulation, while increasing RAB7 levels, suggesting enhanced late-endosomal recycling. VPS35-positive vesicles were redistributed away from the nucleus, indicating restored intracellular trafficking dynamics. In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes. Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis. Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.
    DOI:  https://doi.org/10.1186/s40478-025-02096-8
  2. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2516103122
    Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity.
    Ana P Verduzco Espinoza, Na Na, Loraine Campanati, Priscilla Ngo, Kristin K Baldwin, Hollis T Cline.
      Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimer's disease (AD), with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor for AD, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media (CM) from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial CM driving greater neuronal activity than APOE3 CM. Both APOE3 and APOE4 neurons increase network activity in response to CM treatments, while APOE4 neurons uniquely increase presynaptic puncta in response to APOE4 microglial CM. CM-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Finally, increased network activity is accompanied by increased lipid droplet (LD) metabolism, and blocking LD metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal LDs in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.
    Keywords:  APOE4; Alzheimer’s disease; exosomes; lipid droplets; microglia
    DOI:  https://doi.org/10.1073/pnas.2516103122
  3. Elife. 2025 Sep 10. pii: RP102269. [Epub ahead of print]13
    The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids.
    David Saeb, Emma E Lietzke, Daisy I Fuchs, Emma C Aldrich, Kimberley D Bruce, Kayla G Sprenger.
      The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer's disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of human (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in modulating the dynamics of the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the 'Expanded Surface 2,' which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding frequency in the presence of R47H. This suggests that sTREM2's neuroprotective role in AD may, at least in part, arise from the stalk domain's ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD.
    Keywords:  TREM2; alzheimer's disease; computational biology; human; immunology; inflammation; molecular dynamics; phospholipids; systems biology
    DOI:  https://doi.org/10.7554/eLife.102269
  4. J Neurochem. 2025 Sep;169(9): e70228
    14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.
    William J Stone, Frank Sanders Pair, Roschongporn Ekkatine, Mary Gannon, Kasandra Scholz, Rudradip Pattanayak, Rohma Syed, Talene A Yacoubian.
      Microglia, the resident immune cells of the central nervous system (CNS), are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson's disease (PD). 14-3-3 proteins act as molecular hubs to regulate protein-protein interactions, which are involved in numerous cellular functions, including cellular signaling, protein folding, and apoptosis. We previously revealed decreased 14-3-3 levels in the brains of human subjects with neurodegenerative diseases. In this study, we examined the role of 14-3-3 proteins in the microglial proinflammatory response to lipopolysaccharide (LPS). We found that LPS treatment induced 14-3-3 protein levels within 6 hours. With the use of BV02 and dimeric fourteen-three-three peptide inhibitor (difopein), a small molecule and peptide inhibitor of 14-3-3 protein-protein interactions, respectively, we found a dramatic increase in microglial activation markers in both immortalized BV-2 microglial cells and in primary mouse microglia. Both 14-3-3 inhibitors also increased LPS-induced microglial phagocytosis, lysosomal proteolysis, and cytokine release in primary microglia. In contrast, chemotaxis toward the cellular damage stimulus, adenosine triphosphate (ATP), was diminished with 14-3-3 inhibition. Inhibition of 14-3-3's hastened LPS-induced activation of the nuclear factor-kB (NF-κB) signaling pathway, as measured by its nuclear translocation. 14-3-3's reduced activation of the NF-κB pathway by binding and inhibiting the release of IκB kinase beta (IKKβ). Disruption of 14-3-3's binding to IKKβ with BV02 or difopein increased the downstream phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα). Collectively, our findings suggest 14-3-3 proteins play a critical role in the regulation of inflammatory responses in microglia and may serve as potential targets for immunotherapy of CNS diseases.
    Keywords:  14‐3‐3 proteins; Parkinson's disease; inhibitor of NF‐κB alpha; liposaccharide; microglia; nuclear factor‐kB
    DOI:  https://doi.org/10.1111/jnc.70228
  5. Commun Biol. 2025 Sep 09. 8(1): 1339
    Contrasting contribution of resident and repopulated brain macrophages in sustaining sleep-wake circuitry.
    Ali Seifinejad, Mojtaba Bandarabadi, Meriem Haddar, Saskia Wundt, Mehdi Tafti, Anne Vassalli, Abbas Khani, Gianni Monaco.
      Sleep is a complex behavior regulated by various brain cell types. However, the roles of brain-resident macrophages, including microglia and CNS-associated macrophages (CAMs), particularly those derived postnatally, in sleep regulation remain poorly understood. Here, we investigated the effects of resident (embryo-derived) and repopulated (postnatally derived) brain-resident macrophages on the regulation of vigilance states in mice. We found that depletion in resident brain macrophages caused increased sleep in the active period, but reduced its quality, reflected in reduced power of brain sleep oscillations. This was observed both for the Non-REM and REM sleep stages. Subsequent repopulation by postnatal brain macrophages resulted in altered, but not fully restored, sleep-wake patterns and additionally induced sleep fragmentation. Furthermore, brain macrophage depletion caused excitatory-inhibitory synaptic imbalance, which was resistant to repopulation, and led to increased inhibitory synapses. At the metabolite level, the distinct metabolite profile induced by brain macrophage depletion largely returned to normal after repopulation. Our findings suggest a so far largely unknown interaction between brain-resident macrophages and sleep and highlight functional differences between resident and postnatally-derived repopulated brain macrophages, paving the way to future exploration of the role of brain macrophages of different origin in sleep disorders and synaptic connectivity.
    DOI:  https://doi.org/10.1038/s42003-025-08781-7
  6. Dev Cell. 2025 Sep 10. pii: S1534-5807(25)00532-5. [Epub ahead of print]
    Early microglia progenitors colonize the embryonic CNS via integrin-mediated migration from the pial surface.
    Philippe Petry, Alexander Oschwald, Simon Merkt, Thien-Ly Julia Dinh, Geoffroy Andrieux, Cylia Crisand, Hannah Botterer, Elisa Nent, Neil Paterson, Monique Havermans, Roman Sankowski, Oliver Schilling, Melanie Boerries, Lukas Amann, Olaf Groß, Andreas Schlitzer, Marco Prinz, Tim Lämmermann, Katrin Kierdorf.
      Macrophage progenitors colonize their anatomical niches in the central nervous system (CNS) in distinct pre- and postnatal waves. Microglia progenitors originate from early erythromyeloid progenitors in the yolk sac and enter the murine CNS around embryonic day (E)9.5. While their developmental origin is well established, the molecular mechanisms guiding CNS colonization are not yet resolved. Using transcriptomic and proteomic approaches, we identified potential factors involved in this process. Microglia progenitors showed a distinct integrin surface profile and transmigrate along the extracellular matrix (ECM)-enriched pial surface into the CNS, pointing to a mesenchyme-to-CNS migration route. Loss of the integrin adaptor protein talin-1 in microglia progenitors led to a reduced CNS colonization, whereas macrophage progenitors in the surrounding mesenchyme remained unchanged. Overall, our data suggest that microglial progenitors enter the CNS parenchyma via talin-1-mediated migration from the surrounding mesenchyme through the ECM-enriched pial surface.
    Keywords:  embryonic microglia; immune development; integrins; macrophage progenitor migration; microglia; microglia development; microglia progenitor recruitment
    DOI:  https://doi.org/10.1016/j.devcel.2025.08.012
  7. Alzheimers Dement. 2025 Sep;21(9): e70528
    Metabolic dysregulation in Alzheimer's disease: A brain metabolomics approach.
    Anke Hüls, Youran Tan, Emma Casey, Zhenjiang Li, Marla Gearing, Allan I Levey, James J Lah, Aliza P Wingo, Dean P Jones, Douglas I Walker, Thomas S Wingo, Donghai Liang.
       INTRODUCTION: This study aimed to identify specific biological pathways and molecules involved in Alzheimer's disease (AD) neuropathology.
    METHODS: We conducted cutting-edge high-resolution metabolomics profiling of 162 human frontal cortex samples from the Emory Alzheimer's Disease Research Center (ADRC) brain bank with comprehensive neuropathological evaluations.
    RESULTS: We identified 155 unique metabolic features and 36 pathways associated with three well-established AD neuropathology markers. Of these, 18 novel metabolites were confirmed with level 1 evidence, implicating their involvement in amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and metabolism of cofactors and vitamins in AD neuropathology. Genetic variability influenced these associations, with non-carriers of the apolipoprotein E (APOE) ε4 allele showing stronger perturbations in metabolites including glucose and adenosine 5'-diphosphoribose.
    DISCUSSION: This study demonstrates the potential of high-resolution metabolomic profiling in brain tissues to elucidate molecular mechanisms underlying AD pathology. Our findings provide critical insights into metabolic dysregulation in AD and its interplay with genetic factors.
    HIGHLIGHTS: This is one of the largest untargeted metabolomics studies of human brain tissue. 155 metabolic features, and 36 metabolic pathways were linked to Alzheimer's disease (AD) neuropathology. Of these, 18 unique metabolites were confirmed with level 1 evidence. Glucose and adenosine 5'-diphosphoribose identified as key metabolic alterations in AD.
    Keywords:  Alzheimer's disease; amino acid metabolism; carbohydrate metabolism; high‐resolution metabolomics; lipid metabolism; metabolism of cofactors and vitamins; neuropathology; nucleotide metabolism; untargeted metabolomics
    DOI:  https://doi.org/10.1002/alz.70528
  8. J Alzheimers Dis. 2025 Sep 12. 13872877251374353
    Neuroinflammation and Alzheimer's disease: Unravelling the molecular mechanisms.
    Aniket Kakkar, Harpreet Singh, Bhuvnesh Kumar Singh, Arvind Kumar, Arun Kumar Mishra, Hitesh Chopra.
      Alzheimer's disease (AD), the most prevalent form of dementia, is pathologically defined by amyloid-β (Aβ) plaques, neurofibrillary tangles, synaptic loss, and progressive neuronal degeneration. Increasing evidence highlights neuroinflammation as a central and modifiable factor in AD pathogenesis. This review critically explores the roles of microglia and astrocytes in mediating neuroinflammatory cascades, emphasizing their dual protective and detrimental functions. Microglial activation and astrocytic polarization into A1 (neurotoxic) and A2 (neuroprotective) subtypes are discussed alongside their contributions to Aβ clearance, tau pathology propagation, and synaptic dysfunction. The disruption of the blood-brain barrier, activation of inflammasome pathways such as NLRP3, and release of cytokines and chemokines exacerbate chronic inflammation and neurodegeneration. Advances in single-cell transcriptomics and lipidomics have revealed glial heterogeneity and novel molecular targets, including disease-associated microglia. Genetic risk factors like apolipoprotein E (APOE) and TREM2 variants further modulate inflammatory responses. Emerging therapeutic strategies, including non-steroidal anti-inflammatory drugs, monoclonal antibodies, and targeted immunomodulators, hold promise for modifying disease progression. Overall, precise targeting of neuroinflammatory pathways offers a compelling avenue for future AD therapies.
    Keywords:  Alzheimer's disease; NLRP3 inflammasome; amyloid-β; astrocytes; blood–brain barrier; microglia; neuroinflammation; tau pathology
    DOI:  https://doi.org/10.1177/13872877251374353
  9. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2500116122
    Microglia contribute to bipolar depression through Serinc2-dependent phospholipid synthesis.
    Ying-Han Wang, Chong-Lei Fu, Lin-Bo Chen, Chu-Yi Zhang, Jian-Shan Chen, Qiao-Ming Zhang, Yirui Liang, Rui-Lan Yang, Yu Li, Ya-Ni Zhang, Yi-Nuo Han, Zhen-Liang Yuan, Yi-Ni Chen, Haimei Li, Yanmeng Pan, Shaohua Hu, Ming Li, Li-Ping Cao, Jun Yao.
      Although clinical research has revealed microglia-related inflammatory and immune responses in bipolar disorder (BD) patient brains, it remains unclear how microglia contribute to the pathogenesis of BD. Here, we demonstrated that Serinc2 is associated with susceptibility to BD and showed a reduced expression in BDII patient plasma, which correlated with the disease severity. Using induced pluripotent stem cell (iPSC) models of sporadic and familial BDII patients, we found that Serinc2 expression showed deficits in iPSC-derived microglia-like cells, resulting in decreased synaptic pruning. Further, combining the microglia-specific Serinc2-deficient mouse and iPSC-microglia models, we found that microglial Serinc2 deficits functioned through attenuating the synthesis of serine-related phospholipids in the plasma membrane, thus resulting in depression-like behavioral abnormalities in the animals. Finally, we showed that the Serinc2-dependent lipid deficits diminished microglial membrane CR3 formation to interrupted synaptic pruning signals from neurons. Therefore, our results indicated that Serinc2 deficits in microglia might contribute to the pathogenesis of BD.
    Keywords:  Serinc2; bipolar disorder; induced pluripotent stem cell; mental disorder; microglia
    DOI:  https://doi.org/10.1073/pnas.2500116122
  10. Sci Transl Med. 2025 Sep 10. 17(815): eadp7047
    Human myelinated brain organoids with integrated microglia as a model for myelin repair and remyelinating therapies.
    Simona Lange, Martin Ebeling, Athéna Loye, Florian Wanke, Juliane Siebourg-Polster, Tania J J Sudharshan, Franziska Völlmy, Jakub Kralik, Bérengère Vidal, Kerstin Hahn, Lynette C Foo, Jan Hoeber.
      Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are essential for the formation of myelin sheaths and pivotal for maintaining axonal integrity and conduction. Disruption of these cells and the myelin sheaths they produce is a hallmark of demyelinating conditions like multiple sclerosis or those resulting from certain drug side effects, leading to profound neurological impairments. In this study, we created a human brain organoid comprising neurons, astrocytes, and myelinating oligodendrocytes. By integrating induced pluripotent stem cell-derived microglia, we endowed these myelinated human brain organoids (MHBOs) with immune characteristics. MHBOs with microglia (MHBOs +MG) enabled the investigation of demyelination and remyelination-a process in which myelin sheaths are regenerated-in a human context. After toxin-induced demyelination, we observed a reduction in myelin followed by subsequent self-driven remyelination. Proteomic and transcriptomic analyses provided a molecular signature of demyelination and myelin recovery indicating a central role for microglia in the remyelination process. Furthermore, the application of the pro-remyelinating compounds clemastine, XAV939, and BQ3020 further enhanced remyelination in MHBOs +MG but was ineffective in the absence of microglia. Cross-validation of our findings in mouse cerebellar slice cultures confirmed that the pro-remyelinating compounds were effective ex vivo, suggesting the translational potential of our MHBOs +MG model.
    DOI:  https://doi.org/10.1126/scitranslmed.adp7047
  11. Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01037-X. [Epub ahead of print]44(9): 116266
    Coordination of autophagosome closure and release by the Alzheimer's disease-associated protein BIN1.
    Jennifer E Palmer, Claudia Puri, Ryan S O'Rourke, Sung Min Son, Chun Sang, Yu-Wen Alvin Huang, David C Rubinsztein.
      Autophagosome closure by the endosomal sorting complex required for transport (ESCRT) complex is a prerequisite for their dynamin 2 (DNM2)-dependent release from the recycling endosome and subsequent lysosomal clearance. However, the mechanism that coordinates autophagosome closure and release is unknown. We identified that the Alzheimer's disease-associated protein bridging integrator 1 (BIN1) is a critical mediator of this coordination. Prior to autophagosome closure, BIN1 is held at autophagosomes by ESCRT-III and inhibits DNM2. Once the autophagosome has closed and ESCRT-III disassembles, BIN1 is released, removing the inhibition of DNM2. This mechanism provides insight into the functional consequences of increased BIN1 expression, as this occurs in microglia with Alzheimer's disease risk-associated polymorphisms. We find that the overexpression of BIN1 microglial isoforms inhibits DNM2-mediated autophagosome release and autophagic clearance. This provides a coherent explanation for the increased Alzheimer's disease risk associated with BIN1, as impaired microglial autophagy alters phagocytosis and is associated with microglial senescence and neuroinflammation.
    Keywords:  Alzheimer’s disease; BIN1; CP: Cell biology; CP: Neuroscience; DNM2; ESCRT-III; autophagy; microglia
    DOI:  https://doi.org/10.1016/j.celrep.2025.116266
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