bims-micgli Biomed News
on Microglia
Issue of 2026–07–19
fifty-four papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Lymphoid-like Suppressive Microglia in Alzheimer's Disease: A New Neuroimmune Regulatory Axis?
  2. Young Adult Microglial Deletion of C1q Reduces Engulfment of Synapses and Partially Mitigates Cognitive Impairment in an Aggressive Alzheimer's Disease Mouse Model.
  3. Breaking the glial loop: astrocytic PAD2 and citrullinated vimentin drive microglial dysfunction in Alzheimer's disease.
  4. Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice.
  5. VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7.
  6. Loss of m6A unmasks a senescence-associated inflammatory program in human microglia.
  7. Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.
  8. PLX3397 Reshapes Hepatic Lipid Metabolism Independent of Microglial Depletion.
  9. Disruption of temporo-parietal network in Alzheimer's disease and its association with memory impairment.
  10. Human Microglial Molecular Alterations in Aging and Alzheimer's Disease.
  11. Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation.
  12. Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.
  13. Astrocytic lipid dysregulation as an early driver of neurodegeneration.
  14. CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.
  15. Loss of TREM2 is associated with altered microglial responses and inhibitory synaptic changes after closed head injury.
  16. Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer's, CADASIL, and Traumatic Brain Injury.
  17. Mapping and manipulating aged and senescent microglia.
  18. Cell-type signatures of Alzheimer's disease shared across population groups.
  19. TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.
  20. Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.
  21. CD4+ T cells reactive to Epstein-Barr virus late lytic antigens are enriched in individuals with multiple sclerosis.
  22. Microglia integrated neural spheroids enable neuroinflammatory responses and correct network dysfunction induced by alpha-synuclein mutation.
  23. Amygdala astrocytes encode anxiety states.
  24. Genetic Deletion of Adenosine A2A Receptors Attenuates Aged-Related Alterations of Glial Cells Morphology and of Inflammasome in the Hippocampus and Prefrontal Cortex of Mice.
  25. Astrocyte exosomes shield retina from ischemia via CaMKII-autophagy.
  26. Microglia prune developing cortical blood vessels through PD-1 signaling.
  27. Varicose projection astrocytes: Conserved reactive cells in brain pathology.
  28. Short-Chain Fatty Acid-Dependent Neuroimmune Regulation in Autism Spectrum Disorder Pathogenesis.
  29. The Microglial Protein sTREM2 Inhibits the Bacterial Functional Amyloid CsgA and Suppresses Amyloid-Dependent Biofilm Formation.
  30. Decoding the PI3K/Akt/mTOR-JAK/STAT signaling axis in multiple sclerosis: mechanistic crosstalk and therapeutic opportunities.
  31. ASB2 inhibits lipid accumulation to promote ILC1 homeostatic fitness and anti-tumor immunity in the mouse liver.
  32. FPR2 deficiency alleviates LPS-induced depressive-like behaviors in mice by suppressing the microglial CSF1/NLRP3 inflammasome pathway.
  33. Neuroplasticity and immune system are related to altered grey matter networks: a cohort study in sporadic Alzheimer's disease.
  34. The complex lipidome as a driver of tissue-specific pathology in adrenoleukodystrophy.
  35. Autophagy maintains high endothelial venule identity and function during inflammation.
  36. Targeting the microglial phosphatidylethanolamine synthesis pathway promotes GABARAP-associated phagocytosis and Aβ clearance in Alzheimer's disease.
  37. A BRD4/p300/SP1 epigenetic cascade drives microglial P2X4R transcription and promotes neuropathic pain.
  38. CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.
  39. STAT6 Targets the Autophagy Pathway to Regulate Microglial Senescence in Cognitive Impairment Caused by Cerebral Small-Vessel Disease.
  40. Early Alzheimer´s disease blood biomarkers are associated with a higher risk for postoperative long-term cognitive decline: Insights from the FINDERI study.
  41. Metabolic Reprogramming of Macrophages Plays a Dual Role in Periodontitis: From Pathogenesis to Therapy.
  42. APOE4 genotype and old age interact to impact cerebrovascular function, brain volume, and neuroinflammation in mice.
  43. Iron overload suppresses LKB1 and induces IL36G anti-tumor immunity in PDAC metastasis.
  44. Dendritic cells control tertiary lymphoid structure development and maintenance in cancer.
  45. Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy.
  46. Air-Liquid interface midbrain organoids model the pathological features of Parkinson's disease.
  47. Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.
  48. Anti-amyloid nanobody-Fc fusion protein drives potent amyloid clearance through microglial recruitment.
  49. Analysis of gene co-expression connectivity dynamics implicates aberrant neuron-oligodendroglia interactions in schizophrenia.
  50. Gut microbe-derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice.
  51. Medial entorhinal-hippocampal desynchronization parallels the emergence of memory impairment in a mouse model of Alzheimer's disease pathology.
  52. Metabolic reprogramming in Alzheimer's disease: Interaction between receptor tyrosine kinase signaling, noncoding RNAs, and Neuron-Glia energy networks.
  53. Distinct molecular subgroups in pediatric and young-onset meningiomas require age-adapted risk stratification.
  54. EXPRESS: Single-Cell Analysis of Microglia and Monocyte Dynamics Uncovers Distinct TNF-driven Neuroimmune Signatures in Humans after Intracerebral Hemorrhage.
  1. Cells. 2026 Jun 24. pii: 1151. [Epub ahead of print]15(13):
    Lymphoid-like Suppressive Microglia in Alzheimer's Disease: A New Neuroimmune Regulatory Axis?
    James Chmiel, Wiktor Gawełczyk, Julia Soczyńska, Jerzy Leszek.
      Microglia are central regulators of Alzheimer's disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer 's-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement activation, astrocyte signaling, aging, and immune genetic risk. Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness. Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions. This review examines the emerging concept that partial, plaque-associated reduction in PU.1 may enable a distinct lymphoid-like immunoregulatory microglial program marked by CD28 expression. Recent evidence suggests that PU.1-low CD28-positive microglia may restrain neuroinflammation and amyloid pathology, raising the possibility that Alzheimer's plaques induce not only inflammatory and phagocytic microglial responses, but also endogenous suppressive programs that limit tissue damage. We discuss this proposed PU.1/CD28 regulatory axis in relation to disease-associated microglia, TREM2-APOE signaling, complement-mediated synapse loss, antigen-presentation pathways, plaque-niche biology, and therapeutic microglial reprogramming. We also highlight major unresolved questions, including whether PU.1-low CD28-positive microglia are present and functional in human Alzheimer's disease, whether they are specific to amyloid-rich niches or extend to tau and mixed pathologies, and how such states could be safely manipulated without disrupting essential immune surveillance. We propose that lymphoid-like suppressive microglia represent a promising but still unproven framework for understanding protective neuroimmune regulation in Alzheimer's disease and for developing state-specific microglial therapies.
    Keywords:  APOE; Alzheimer’s disease; CD28; PU.1; SPI1; TREM2; amyloid plaques; complement; disease-associated microglia; immunoregulatory microglia; lymphoid-like microglia; microglia; microglial heterogeneity; microglial reprogramming; neuroimmune regulation; neuroinflammation; plaque-associated microglia; single-cell transcriptomics; spatial transcriptomics; suppressive microglia
    DOI:  https://doi.org/10.3390/cells15131151
  2. Glia. 2026 Sep;74(9): e70189
    Young Adult Microglial Deletion of C1q Reduces Engulfment of Synapses and Partially Mitigates Cognitive Impairment in an Aggressive Alzheimer's Disease Mouse Model.
    Tiffany J Petrisko, Shu-Hui Chu, Angela Gomez-Arboledas, Blossom Zhang, Andrea J Tenner.
      C1q is a multifunctional protein, including its role as the initiating protein of the classical complement cascade. While classical pathway activation is involved in synaptic pruning during nervous system development, it also contributes to inflammation and cognitive decline in Alzheimer's disease (AD). Constitutive genetic C1q deficiency has been shown to reduce glial activation and attenuate neuronal loss in AD mouse models, but the specific contributions of microglial C1q to AD pathology while avoiding deficits during post-natal development remain unaddressed. To dissect specific role(s) of microglial C1q in AD progression, we crossed the Cx3cr1CreERT2 mouse model that deletes C1q from microglia in young adulthood (8 weeks of age) to the aggressive Arctic48 (Arc) amyloidosis mouse model. At 10 months, young adult microglial C1q deletion (Arc C1qΔMG) was associated with improved spatial memory performance, despite unchanged amyloid plaque burden. Furthermore, Arc C1qΔMG mice exhibited reduced hippocampal C3 protein levels without altering C3 mRNA. No changes were observed in C5aR1, astrocyte GFAP, or microglial Iba1 protein expression. However, Arc C1qΔMG mice demonstrated region specific reductions in microglial synaptic engulfment, alongside decreased phagolysosome-associated amyloid in both microglia and astrocytes, and reduced hippocampal amyloid compaction. These findings support a role for C1q in astrocytic C3 induction and the engulfment of both synapses and amyloid. Importantly, young adult microglial C1q inhibition confers cognitive benefits without exacerbating amyloid pathology, suggesting a therapeutic window in which targeting microglial C1q may help preserve synaptic integrity and modulate the neuroinflammatory processes during the later stages of AD.
    Keywords:  Alzheimer's disease; C1q; amyloid; cognition; complement; microglia; synapse
    DOI:  https://doi.org/10.1002/glia.70189
  3. Mol Neurodegener. 2026 Jul 13. pii: 35. [Epub ahead of print]21(1):
    Breaking the glial loop: astrocytic PAD2 and citrullinated vimentin drive microglial dysfunction in Alzheimer's disease.
    Jeff Y L Lam, Guojun Bu.
      Zhang et al. reveal that astrocytic PAD2-mediated citrullination of vimentin drives a TLR4-dependent pro-inflammatory loop in microglia, linking glial crosstalk to impaired amyloid clearance and identifying a potential therapeutic and biomarker pathway in Alzheimer's disease.
    Keywords:  Alzheimer’s disease; Astrocytes; Glial crosstalk; Microglia; Protein post-translational modification; Vimentin
    DOI:  https://doi.org/10.1186/s13024-026-00974-w
  4. Mol Neurodegener. 2026 Jul 16.
    Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice.
    Hayk Davtyan, Sarah Naguib, Yuliya Voskobiynyk, Jean Paul Chadarevian, Joia K Capocchi, Jeannie L Giacchino, Ghazaleh Eskandari-Sedighi, Vivianna DeNittis, Jeremy B Ford, Ani Agababian, Jasmine Nguyen, Alina L Chadarevian, Madison S Sutherland, Sepideh Kiani Shabestari, Kayla Tran, Bret Holt, Alissa L Nana, Jiasheng Zhang, Salvatore Spina, Man Ying Wong, Lea T Grinberg, William W Seeley, Eric Huang, Claire D Clelland, Shiaoching Gong, Li Fan, Jeanne T Paz, Mathew Blurton-Jones, Li Gan.
      Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (Grn)-deficient mice. We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.
    DOI:  https://doi.org/10.1186/s13024-026-00978-6
  5. Glia. 2026 Sep;74(9): e70203
    VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7.
    Yue Liang, Tong Chang, Leping Yan, Jiayi Li, Yihe Zhang, Jianhua Ding, Yinquan Fang, Gang Hu.
      Microglial dysfunction and aberrant lipid metabolism are emerging as key contributors to Parkinson's disease (PD) pathogenesis. However, the specific role and regulation of lipid droplets (LDs) within microglia remain poorly defined. In this study, we employed MPTP- and LPS-induced PD mouse models and an in vitro system utilizing astrocyte-conditioned medium to model disease-relevant lipid stress and found enhanced LD accumulation in microglia. VPS35 expression was decreased in microglia, correlating with elevated microglial LD levels in PD mouse models. We then performed genetic manipulations (knockdown and overexpression) of VPS35, including the PD-associated D620N mutant, in primary microglia and assessed LD accumulation, phagocytic function, inflammatory responses, and integrated stress pathways. We showed that VPS35 knockdown exacerbated the accumulation of LDs in microglia. Conversely, VPS35 overexpression ameliorated LD formation, improved phagocytic function, and reduced inflammatory and integrated stress responses in microglia. The PD-related VPS35[D620N] mutation abolished these protective effects. We further found that VPS35 interacts with Rab7 to maintain lysosomal function, and the D620N mutation disrupts this interaction, leading to defective LD clearance. Our findings reveal VPS35 dysfunction as a key pathogenic mechanism in PD, where the D620N mutation disrupts microglial lipid handling to promote disease progression, thereby nominating VPS35 restoration as a promising therapeutic strategy.
    Keywords:  Parkinson's disease; VPS35; astrocyte; lipid droplet; lysosome; microglia
    DOI:  https://doi.org/10.1002/glia.70203
  6. bioRxiv. 2026 Jul 08. pii: 2026.07.06.736874. [Epub ahead of print]
    Loss of m6A unmasks a senescence-associated inflammatory program in human microglia.
    Deepak Pathak, Rashmi Basavaraj, Lina Sun, Yi-Lan Weng.
      Chronic microglial inflammation and cellular senescence are hallmarks of the aging brain, yet the molecular events that lock microglia into durable inflammatory states remain poorly understood. Prior studies using genetic manipulation of METTL3 have implicated the RNA modification N6-methyladenosine (m6A) in senescence. However, because METTL3 also has m6A-independent functions, loss-of-function approaches cannot distinguish whether senescence arises from reduced m6A itself or from broader disruption of METTL3-dependent pathways. This question is further complicated in microglia, where METTL3 has been reported to promote acute inflammatory activation, suggesting that m6A may have context-dependent effects on immune state. Whether sustained reduction of m6A is sufficient to drive microglial senescence has therefore remained unresolved. Here, we show that selective catalytic inhibition of METTL3 with STM2457 lowers global m6A and is sufficient to induce a senescence-like inflammatory state in human HMC3 microglia. This state includes increased senescence-associated β-galactosidase activity, elongated cellular morphology, reduced proliferation, Lamin B1 loss, and remodeling of nuclear architecture. Transcriptomic profiling revealed suppression of mitotic gene programs together with a SASP-like inflammatory output marked by NF-κB and interferon signatures. Rather than causing broad transposable-element derepression, m6A inhibition promoted cytoplasmic double-stranded RNA accumulation and a selective HERVK-associated response. These findings support a model in which m6A helps preserve microglial homeostasis by limiting immunogenic RNA accumulation and senescence-associated inflammatory remodeling. Together, our study identifies m6A as a safeguard against microglial senescence and suggests that reduced m6A-dependent RNA regulation may contribute to chronic inflammatory remodeling in the aging brain.
    DOI:  https://doi.org/10.64898/2026.07.06.736874
  7. Nat Aging. 2026 Jul;6(7): 1417-1436
    Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.
    Chase M Carver, Paul T Gomez, Sonia L Rodriguez, James T Redden, Amanda S Latham, Yooree Ha, Jennifer M Kachergus, Yi Liu, Ji Shi, Tommy Tran, Liguo Wang, Simon Melov, E A Thompson, Marissa J Schafer.
      Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, immunolabeling, GeoMx digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3). Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3+ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.
    DOI:  https://doi.org/10.1038/s43587-026-01154-7
  8. Neurosci Bull. 2026 Jul 13.
    PLX3397 Reshapes Hepatic Lipid Metabolism Independent of Microglial Depletion.
    Jiahui Lyu, Wang Cheng, Chun-Yue Li, Jiayan Wang, Xiaorong Zhang, Huifang Lou, Yalin Hu, Zhihua Gao, Shumin Duan, Kelei Cao.
      Colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX5622 and PLX3397 (pexidartinib), are widely used for in vivo microglial depletion and for investigating microglial functions and therapeutic potential. Although CSF1R inhibitor-based studies have uncovered important roles for microglia in processes, such as anesthesia, addiction, and obesity, whether the resulting phenotypes reflect microglial depletion alone remains increasingly debated. Our previous work has shown that PLX5622 activates hepatic constitutive androstane receptor (CAR)-dependent xenobiotic metabolism, altering the metabolism of anesthetics and addictive drugs, and amplifying apparent microglial phenotypes. Whether other CSF1R inhibitors, particularly the FDA-approved PLX3397, exert systemic metabolic effects that may influence the interpretation of brain phenotypes remains unknown. Here, we demonstrate that PLX3397 exerts hepatic metabolic effects that are mechanistically distinct from those induced by PLX5622. Although PLX3397 only weakly affects xenobiotic metabolism, it markedly enhances endogenous hepatic lipid metabolism, inducing a fasting-like state characterized by increased lipid utilization and ketogenesis despite the absence of nutrient deprivation. By uncovering previously unrecognized peripheral effects of PLX3397, our findings identify brain-periphery interactions as a potential source of confounding in studies of microglial function. These results suggest that systemic metabolic effects should be carefully considered when interpreting neural or behavioral phenotypes in pharmacological microglia depletion paradigms.
    Keywords:  Lipid metabolism; Microglial depletion; PLX3397·PLX5622; Xenobiotic metabolism
    DOI:  https://doi.org/10.1007/s12264-026-01668-5
  9. Alzheimers Res Ther. 2026 Jul 15. pii: 166. [Epub ahead of print]18(1):
    Disruption of temporo-parietal network in Alzheimer's disease and its association with memory impairment.
    Yanin Suksangkharn, Björn Hendrik Schott, Peter Zeidman, Niklas Vockert, René Lattmann, Hartmut Schütze, Renat Yakupov, Oliver Peters, Julian Hellmann-Regen, Lukas Preis, Ersin Ersözlü, Josef Priller, Eike Jakob Spruth, Janna Beckmann, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Claudia Bartels, Ayda Rostamzadeh, Wenzel Glanz, Enise I Incesoy, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Christoph Laske, Annika Spottke, Marie Kronmüller, Frederic Brosseron, Falk Lüsebrink, Matthias Schmid, Luca Kleineidam, Melina Stark, Stefan Hetzer, Peter Dechent, Frank Jessen, Anne Maass, Emrah Düzel, Gabriel Ziegler.
      Alzheimer's disease (AD) is characterised by the accumulation of β-amyloid (Aβ) and tau proteins, resulting in neurodegeneration and cognitive decline. Although Aβ and tau disrupt synaptic function, the association linking these molecular pathologies to network-level dysfunction and memory impairment remains poorly understood. Here, we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity related to memory encoding, which may provide a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from 205 participants in the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) across the AD spectrum. Effective connectivity was assessed using Dynamic Causal Modelling (DCM) of task-fMRI data, focusing on the parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU)-regions central to memory encoding. Disruptions in connectivity between temporal and parietal lobes were associated with both memory impairment and indices of AD pathology. Specifically, reduced positive effective connectivity from the PCU to the PPA and from the HC to the PCU were linked to higher p-tau-181 levels, with an amplification effect observed in the presence of amyloid accumulation for the latter connectivity. The disruption from the PCU to the PPA was found to be associated with decreased memory performance. Together, these findings indicate that temporo-parietal connectivity is associated with both AD molecular pathology and, for a subset of connections, with memory performance.
    Keywords:  Alzheimer's disease; Beta-amyloid; Memory impairment; Neurodegeneration; Synaptic aberration; Tau
    DOI:  https://doi.org/10.1186/s13195-026-02138-w
  10. Cells. 2026 Jun 25. pii: 1159. [Epub ahead of print]15(13):
    Human Microglial Molecular Alterations in Aging and Alzheimer's Disease.
    Karol Ann T Baldo, Elisa Gozlan, Emmanuel O Chidebe, Ifeoluwa Awogbindin, Marina Ocaña Prieto, Leslie Michelle Dalmacio, Benneth Ben-Azu, Dan Frenkel, Marie-Ève Tremblay.
      Microglia, the resident innate immune cells of the central nervous system, are central players in brain development, healthy aging, and degenerative pathology, including Alzheimer's disease (AD). Aging is a major risk factor for AD, and various studies have identified alterations in microglial molecular signatures and morphological patterns that overlap with microglial states during aging. However, the mechanisms underlying the divergence of aging trajectories toward disease remain unclear. Thus, understanding the molecular changes in microglia during aging and AD pathology is crucial to elucidating the mechanisms that drive disease progression. In this review, we examine current advances in understanding the phenotypic alterations in human microglia, highlighting gene signatures and morphological changes that may aid in defining microglia's molecular and functional programs in healthy aging and over the course of AD. We further explore the roles of oxidative stress and cellular senescence in driving the development of a chronic reactive state in microglia during aging, which may also contribute to the complex process underlying the onset and progression of AD pathology. This review highlights the advancements in therapeutic strategies focused on targeting pertinent pathological microglial changes during aging and in disease to mitigate the AD neurodegenerative process.
    Keywords:  Alzheimer’s disease; aging; human; inflammation; microglia; oxidative stress; senescence
    DOI:  https://doi.org/10.3390/cells15131159
  11. J Neuroinflammation. 2026 Jul 13.
    Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation.
    Mingyue Zou, Tengyu Zhao, Weidong Wu, Jian Zhang, Pengyu Pan, Jingdong Yan, Quan Li, Yanyan Zhou.
      AD is a complex neurodegenerative disorder characterized by chronic neuroinflammation. Microglia, the brain's resident immune cells, centrally regulate AD pathophysiology. Recent studies have highlighted microglial mitophagy as an important interface linking mitochondrial quality control to innate immune responses.Intact mitophagy facilitates the timely clearance of damaged mitochondria, thereby limiting the release of mitochondrial DAMPs (e.g., mtDNA and mtROS) and helping restrain aberrant activation of the cGAS-STING pathway and the NLRP3 inflammasome.In the AD pathological milieu, however, factors including Aβ deposition, tau pathology, and genetic risk variants such as TREM2 and APOE4 disrupt mitophagy at multiple levels-from initiation and recognition to lysosomal degradation. This review systematically summarizes the molecular regulatory network of microglial mitophagy, with a particular focus on the mechanisms by which AD-associated pathological factors impair this process. We further discuss potential mechanisms through which mitophagic dysfunction may contribute to the amplification of neuroinflammation, including the release of mitochondrial DAMPs, the reprogramming of TBK1 signaling, and intercellular interactions. Finally, we outline current therapeutic strategies aimed at restoring mitophagy and discuss their potential to modulate neuroinflammatory responses and AD-related pathological processes, while highlighting the challenges and future directions in this emerging field.
    Keywords:  Alzheimer's disease; CGAS-STING; Immunometabolism; Microglia; Mitophagy; NLRP3 inflammasome; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-026-03946-5
  12. J Neuroinflammation. 2026 Jul 17.
    Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.
    Xiaolu Tang, Rui Chen, Jiawei Xing, Qing Huang, Lv Luo, Chaoyue Ouyang, Fubin Ma, Jie Wen, Jiahao Zhang, Lingyun Kong, Yujie Cai, Yan Wang, Lili Cui.
       BACKGROUND: Current therapies for Alzheimer's disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system.
    METHODS: Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (Aβ) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD.
    RESULTS: LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to Aβ plaques and increased phagocytic clearance. Consequently, treated mice showed reduced Aβ plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming.
    CONCLUSION: Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.
    Keywords:  Alzheimer’s disease (AD); Extracellular vesicles (EVs); Glycolysis; Oxidative phosphorylation; SIRT2
    DOI:  https://doi.org/10.1186/s12974-026-03956-3
  13. Nat Rev Neurol. 2026 Jul 13.
    Astrocytic lipid dysregulation as an early driver of neurodegeneration.
    Woojin Scott Kim, Glenda M Halliday.
      Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.
    DOI:  https://doi.org/10.1038/s41582-026-01238-3
  14. Nat Commun. 2026 Jul 17.
    CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.
    Roger B Dodd, Masahiro Enomoto, Ye Zhou, Kanayo Satoh, Yalun Zhang, Fusheng Chen, Beatrice Acheson, Deniz Ghaffari, Elizabeth Sayn-Wittgenstein, Jamie J Manning, George V Dukas, Ronak Patel, Alondra Schweizer Burguete, Mason J Kralovec, Mamunur Rashid, Jennifer L Hall, Kirstin A Tamucci, Zena Chatila, Minghua Liu, Annie J Lee, Badri N Vardarajan, Mariko F Taga, Sirkku Pollari, Alon Rabinovitch, Cory D Rillahan, Andrey A Bobkov, Eduard Sergienko, William Meadows, Seema Qamar, Suzanne J Randle, Christopher M Johnson, Jean Sevalle, Jennifer Griffin, Christopher Bohm, Mitsuhiko Ikura, Xunde Xian, Joachim Herz, Megan A Kelly, Jennifer West, Sandeep Satapathy, Mark R Wilson, Jonathan A Javitch, Paul E Fraser, David A Bennett, Philip L De Jager, Zvi Fishelson, Dan Frenkel, Wesley B Asher, Elizabeth M Bradshaw, Peter St George-Hyslop.
      Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33M ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33M, but not CD33m. We show that in human monocytes CD33M:CLU binding induces CD33M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33M ectodomain fragment (sCD33M) - absent from CD33m-expressing cells - which could contribute to the role of CD33M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33M axis, highlighting CD33M dimerization and ligand-binding sites as potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-75140-3
  15. Exp Neurol. 2026 Jul 12. pii: S0014-4886(26)00293-1. [Epub ahead of print] 115928
    Loss of TREM2 is associated with altered microglial responses and inhibitory synaptic changes after closed head injury.
    Duan Wang, Donghui Lin, Jiayu Liu, Lingnian Zeng, Haohan Lin, Ningning Chen, Shaofan Chen, Huyao Zhou, Xia Wang, Nong Xiao.
      Closed head injury (CHI) is often considered to cause mild brain injury without overt cortical lesions. However, synaptic pathology following CHI, particularly in different phase, remains poorly understood. In this study, we investigate temporal changes in synaptic protein expression and microglial responses following CHI. Our results show a selective loss of inhibitory presynaptic marker vGAT, accompanied by transient increases in excitatory postsynaptic markers PSD-95 and gephyrin. Notably, these changes occur alongside a peak in microglial activation at 3 days post-injury (dpi). Bulk RNA sequencing analysis identified TREM2 as a prominently upregulated microglia-associated gene during the acute phase of injury. Loss of TREM2 in knockout mice (TREM2-/-) resulted in attenuated microglial activation, impaired accumulation at the injury site, and reduced expression of response-related genes, including Cx3cr1 and Cd68. Additionally, C1q, a key component in synaptic pruning, exhibited altered expression and spatial distribution in TREM2-deficient mice, suggesting a potential TREM2-dependent role in regulating microglial responses and synaptic alterations after CHI. These findings highlight TREM2 as a critical modulator of microglial function and synaptic remodeling following brain injury.
    Keywords:  C1q; Inhibitory synapses; Microglia and TREM2; Synaptic remodeling; Traumatic brain injury; vGAT
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115928
  16. Nat Commun. 2026 Jul 16. pii: 6392. [Epub ahead of print]17(1):
    Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer's, CADASIL, and Traumatic Brain Injury.
    K D Bjørnholm, H Li, F Del Gaudio, G Mocci, W Shao, E Baldisseri, S B Rao, C Lindblad, A Fletcher-Sandersjöö, E Vázquez-Liébanas, R Pietilä, L Muhl, R Jiang, C Kalantzi, J Cheung, S Jin, M Svensson, S A J Lesnik Oberstein, S Syvänen, M A Mäe, R Torp, U Lendahl, H Karlström, E P Thelin, P Nilsson, M Vanlandewijck.
      The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.
    DOI:  https://doi.org/10.1038/s41467-026-75367-0
  17. Nat Aging. 2026 Jul;6(7): 1360-1361
    Mapping and manipulating aged and senescent microglia.
      
    DOI:  https://doi.org/10.1038/s43587-026-01167-2
  18. Nature. 2026 Jul 15.
    Cell-type signatures of Alzheimer's disease shared across population groups.
    Tain Luquez, Jonathan Algoo, Rebecca Chiu, Jason A Mares, Archana Yadav, Matti Lam, Pallavi Gaur, Xiaoying Lai, Dylan I Lee, Fahad Paryani, Rafe Batchelor, Irla Belli, Jordan Henry, Bat Hoter-Ishay, Courteney Mattison, Lindsey Starr, Tsering Lama, Berke Karaahmet, Wenqing Cao, Philip L De Jager, Mariko Taga, Lisa L Barnes, David X Marquez, David A Bennett, Ya Zhang, Vilas Menon.
      Genomic studies at single-cell resolution have identified several cell types associated with clinical and pathological traits in Alzheimer's disease1-9, but have not examined associations that are shared across populations. To bridge this gap, here we use single-nucleus RNA sequencing and assay for transposase-accessible chromatin with sequencing to profile cortical and subcortical regions in post-mortem brain-tissue samples from Latin, white (excluding Latin) and African American (excluding Latin) individuals. Using discrete and continuous dissections of molecular programs, we identify cell-type-specific clusters associated with Alzheimer's disease in a region-specific manner across all three population groups, including microglial (GPNMB+ and CD74+ subgroups), astrocytic (SERPINH1+, CD44+ and WIF1+ subgroups) and neuronal (SST+ GABAergic and superficial-layer glutamatergic) signatures. We also report continuous gene-expression factors in astrocytes and oligodendrocytes that are not captured by discrete cluster assignments, but which show strong associations with disease phenotypes; these factors are enriched for genes associated with annotated functions such as lipid processing and neurotransmitter reuptake. Finally, we find that molecular programs reveal six distinct subgroups of individuals with cognitive impairment that span all three populations, are not captured by neuropathology, and are instead distinguished by molecular signatures that are not universally present but are nonetheless associated with ante-mortem impairment. Overall, our study identifies key cell types and gene programs implicated in Alzheimer's disease that are shared across population groups, and underscores how representative sampling can capture both shared signatures and disease heterogeneity, thereby enabling better prioritization of key cell types for further investigation.
    DOI:  https://doi.org/10.1038/s41586-026-10793-0
  19. Cell Commun Signal. 2026 Jul 15.
    TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.
    Haixia Wang, Ruiming Wen, Emily Parker, Luodan Yang.
      Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical myeloid receptor expressed on the surface of central nervous system microglia, capable of integrating signals from lipids, damage-associated molecular patterns, and abnormal protein aggregates to regulate phagocytosis, metabolic adaptation, inflammatory remodeling, and pathology-associated responses. Accumulating evidence indicates that TREM2 is neither uniformly protective nor uniformly pathogenic; rather, its biological effects are highly context-dependent, governed collectively by disease stage, pathological substrates, cellular compartments, and the local microenvironment. By coupling with TYROBP/DAP12 or DAP10, TREM2 actively drives the state remodeling of pathology-associated microglia. It profoundly influences the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), as well as acute central nervous system injuries, including ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). Concurrently, soluble TREM2 (sTREM2) holds significant potential not only as a biomarker but also as a context-dependent effector molecule actively participating in pathological regulation. This review synthesizes current advancements by focusing on four core themes: the structural and signaling logic of the TREM2 axis; its regulation of disease-associated microglia (DAM) remodeling; the cross-disease significance of sTREM2; and the mechanistic basis for the divergent outcomes observed with TREM2-targeted therapies across different experimental models and disease stages. The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.
    Keywords:  Acute nervous system injury; Central nervous system; Microglia; Neurodegenerative diseases; TREM2; sTREM2
    DOI:  https://doi.org/10.1186/s12964-026-03083-9
  20. Neurobiol Aging. 2026 Jul 10. pii: S0197-4580(26)00122-3. [Epub ahead of print]168 23-36
    Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.
    Maria Giovanna Caruso, Sebastian Dohm-Hansen, Francisco Donoso, Zoë A P Williams, Stefanie Grabrucker, Aonghus Lavelle, Jane A English, Sarah Nicolas, Olivia F O'Leary, Yvonne M Nolan.
      Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been investigated. We hypothesise that peripheral metabolic or protein features are associated with hippocampal vulnerability in middle age. Therefore, young adult and middle-aged rats were assessed for behavioural, proteomic, metabolic, and gut microbiota differences. Proteomic profiling of the hippocampus revealed differential expression of proteins indicative of altered synaptic signalling. Concurrently, adult hippocampal neurogenesis was decreased in middle age. Hippocampal microglia exhibited a lipid rich, inflammatory phenotype in middle age which correlated with poorer memory performance. CSF and serum proteomic and metabolomic analyses identified dysregulated lipid-related pathways potentially contributing to hippocampal vulnerability in middle age. Furthermore, 16S rRNA sequencing revealed reduced abundance of bacteria involved in lipid metabolism regulation. However, faecal microbiota transfer from young to middle aged rats was not sufficient to robustly improve hippocampus-dependent spatial memory. Together, these findings highlight dysfunctional lipid metabolism as a key feature of middle age that may contribute to decline in hippocampal function. Given that the scope for intervention is limited during older age, targeting biomarkers involved in metabolic and lipid homeostasis may be pivotal for the development of pharmacological or lifestyle-based interventions during middle age which could ultimately delay future cognitive ageing.
    Keywords:  CSF; Gut microbiota; Hippocampus; Lipid metabolism; Microglia; Middle age; Neurogenesis
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.07.001
  21. Sci Transl Med. 2026 Jul 15. 18(858): eadz6566
    CD4+ T cells reactive to Epstein-Barr virus late lytic antigens are enriched in individuals with multiple sclerosis.
    Kjetil Bjornevik, João Vitor Mahler, Philippe A Bilodeau, Brit Ellen Rød, Gabriela Romanow, Takahisa Mikami, Monique Anderson, Natasha Bobrowski-Khoury, Huimin Zhu, James Nguyen, Ying Sun, Marcelo Matiello, David Housman, Bardia Nourbakhsh, Kjell-Morten Myhr, Øivind Torkildsen, Ludvig M Sollid, Michael Levy, Natalia Drosu.
      Multiple sclerosis (MS) pathogenesis is linked to Epstein-Barr virus (EBV), but the underlying immune mechanisms remain unclear. Using an optimized T cell assay, we demonstrate that CD4+ T cells from individuals with MS predominantly target EBV viral particle components, specifically the late lytic capsid and glycoprotein antigens, rather than latent antigens. In contrast, the Epstein-Barr nuclear antigen 1 (EBNA1) primarily activated CD8+ T cells. EBV-specific CD4+ T cell responses were twofold higher in individuals with untreated MS compared with healthy controls, whereas responses to other herpesviruses remained similar. Anti-CD20 therapy initiation in treatment-naïve participants reduced these responses, a finding validated in an independent cohort, and eliminated viral shedding in saliva. Our results establish preferential CD4+ T cell reactivity to EBV late lytic antigens as a key feature of MS, providing a framework for developing EBV-targeted therapies, including vaccines and antivirals.
    DOI:  https://doi.org/10.1126/scitranslmed.adz6566
  22. Commun Biol. 2026 Jul 15.
    Microglia integrated neural spheroids enable neuroinflammatory responses and correct network dysfunction induced by alpha-synuclein mutation.
    Jiajing Zhang, Yi Wei Lim, Angelica Medina, Yu-Chi Chen, Yining Irene Wang, Martin Carrasco Carvajal, Marc Ferrer, Emily M Lee.
      Microglia are the primary resident immune cells of the brain, playing both protective and deleterious roles in neurological diseases, which makes them an enticing therapeutic target. Here we developed a Neural Microglia Integrated Multicellular iPSC-derived Cultured Spheroids (NeuroMIMICS) system that enables measurements of both neural network activity and immune responses using human iPSC-derived microglia, astrocytes, and neurons. We validated microglia functionalities in these neural tri-cultures including phagocytic activity, directed motility, and inflammatory responses. RNAseq analysis revealed a phenotypical acquisition of immune functionality via microglia incorporation, supported by increased cytokine production in spheroids challenged with pathogen-like insults. We then demonstrated that the incorporation of healthy microglia corrected alpha-synuclein A53T-mediated dysfunctional phenotypes in the neural spheroids. This work demonstrates a unique immunocompetent functional neural model that is robust and suited for high-throughput screening, laying the groundwork for its application to accelerate the discovery of new therapeutics for neurological diseases.
    DOI:  https://doi.org/10.1038/s42003-026-10696-w
  23. Neuron. 2026 Jul 15. pii: S0896-6273(26)00450-2. [Epub ahead of print]114(14): 2495-2497
    Amygdala astrocytes encode anxiety states.
    Xinzhu Yu, Baljit S Khakh.
      In this issue of Neuron, Ghenissa and colleagues1 show that intracellular Ca2+ signaling within populations of astrocytes in the basolateral amygdala of mice encodes anxiety states that are regulated by noradrenergic signaling through α1 adrenergic receptors. These findings identify amygdala astrocytes as a cellular element contributing to anxiety circuits.
    DOI:  https://doi.org/10.1016/j.neuron.2026.06.004
  24. Glia. 2026 09;74(9): e70197
    Genetic Deletion of Adenosine A2A Receptors Attenuates Aged-Related Alterations of Glial Cells Morphology and of Inflammasome in the Hippocampus and Prefrontal Cortex of Mice.
    Cátia R Lopes, Samira G Ferreira, Rodrigo A Cunha, Paula Agostinho.
      Although brain disorders are the major burden of disease in Western countries and their incidence increases sharply with aging, the biological basis of brain aging is still poorly explored. Glial cells, namely microglia and astrocytes, maintain brain homeostasis and mount neuroinflammation that can contribute to age-related deterioration of brain functions. The purinergic system, particularly adenosine A2A (A2AR) and P2X7 (P2X7R) receptors, modulates glial function and neuroinflammation. The present study aims to investigate how aging affects microglia and astrocytes morphology and the NRLP3 inflammasome complex, a key driver of the inflammatory process, and if the genetic deletion of A2AR has a protective role in inflammaging. We resorted to wild-type and A2AR knockout mice with 3- and 24- month-old to investigate alterations in microglia and astrocytes morphology, in P2X7R, and in related NRLP3 inflammasome components in the hippocampus and prefrontal cortex. Data show that brain aging alters the tridimensional structure of microglia and astrocytes in the hippocampus and prefrontal cortex. Aging decreased the levels of P2X7R and of inflammasome components, NLRP3 and caspase 1, in the hippocampus. Remarkably, A2AR knockout abrogated age-related morphological changes of glial cells in both brain structures. Also, the decreased hippocampal P2X7R levels and the alterations in NLRP3 levels in both hippocampus and cortex, were no longer present in aged A2AR knockout mice. These findings indicate that A2AR might bolster NRLP3 inflammasome activation associated with an age-related neuroinflammation, and A2AR blockade might promote healthy brain aging.
    Keywords:  A2A receptors; NRLP3 inflammasome; P2X7 receptors; aging; astrocytes; brain; microglia
    DOI:  https://doi.org/10.1002/glia.70197
  25. Ann Med. 2026 Dec;58(1): 2702698
    Astrocyte exosomes shield retina from ischemia via CaMKII-autophagy.
    Dan He, Hua Li, Chunling Wei, Chen Chen, Juanjuan Li.
       BACKGROUND: Retinal ischemia-reperfusion (RIR) injury impairs vision through microvascular damage and inflammation. While astrocyte-derived exosomes (ADEs) offer neuroprotection, their role in protecting retinal microvasculature is unclear. This study investigates ADEs' effects on retinal microvascular endothelial cells (RMECs) in RIR.
    METHODS: ADEs were isolated from astrocytes. Mouse RIR and cellular oxygen-glucose deprivation/reoxygenation (OGD/R) models were used. We assessed ADEs' impact on retinal microcirculation, microglial activation, and RMEC function. The roles of neurogranin and the CaMKII-autophagy pathway were examined using inhibitors.
    RESULTS: ADEs, rich in neurogranin, alleviated RIR-induced microvascular damage and suppressed OGD/R-triggered pro-inflammatory microglial activation. This was associated with increased neurogranin, CaMKII phosphorylation, and autophagy in microglia. Consequently, ADEs counteracted the harmful effects of activated microglia on RMEC proliferation, migration, and tube formation. Inhibiting CaMKII or autophagy blocked ADEs' protective benefits without altering neurogranin, placing the CaMKII-autophagy axis downstream.
    CONCLUSION: ADEs protect RMECs from RIR injury by modulating microglial responses via a neurogranin-CaMKII-autophagy mechanism, revealing their therapeutic potential for retinal microvascular protection.
    Keywords:  Astrocyte-derived exosomes (ADEs); CaMKII-autophagy axis; microglia; neurogranin; retinal ischemia-reperfusion (RIR); retinal microvascular endothelial cells
    DOI:  https://doi.org/10.1080/07853890.2026.2702698
  26. Nat Neurosci. 2026 Jul 16.
    Microglia prune developing cortical blood vessels through PD-1 signaling.
    Mengtian Zhang, Yanyan Wang, Runhua Yang, Fen Ji, Sihan Li, Chenxiao Li, Xinghua Zhao, Hong Li, Jianwei Jiao.
      During cerebrovascular development, an initial surplus of vessels is generated and subsequently refined through selective elimination to establish an efficient vascular network. Microglia are pivotal regulators of synaptic refinement and brain circuitry maturation, and despite their close interactions with cerebral vessels, whether and how they contribute to cerebrovascular pruning remains unclear. Here, to address this, we visualized and manipulated microglia-vessel interactions in the frontal cortex of postnatal day 11 mice. We found that microglia progressively approach cerebral vessels and subsequently mediate their pruning. Furthermore, we identify the PD-L1-PD-1 signaling axis as a regulator of microglia-mediated vascular pruning via microglial CD5L secretion. Altogether, our findings uncover a role for microglia in targeting redundant vasculature to facilitate vascular network formation during brain development.
    DOI:  https://doi.org/10.1038/s41593-026-02378-x
  27. Sci Adv. 2026 Jul 17. 12(29): eady8204
    Varicose projection astrocytes: Conserved reactive cells in brain pathology.
    Caterina Ciani, Giulio Pistorio, Simona Giancola, Marika Mearelli, Francesca Emma Mongelli, Delaram Forouzeh, Luana Campos Soares, Marta Gonzalez Martin, Mandi E Lichtenstein, Luca Mio, Elena Christou, Kyle Hastings, Anh Quynh Nguyen Do, Paula Ramos-Gonzalez, Carlos Matute, Ugne Kuliesiute, Sari Elena Dötterer, Gediminas Luksys, Saulius Rocka, Urte Neniskyte, Daniel C Anthony, Marya Ayub, Cinzia Centelleghe, Maria Angeles Arevalo, Jean-Marie Graïc, Francesco Petrelli, Alexei Verkhratsky, Nunzio Iraci, Fabio Cavaliere, Carmen Muñoz-Ballester, Mootaz M Salman, Francesco P Ulloa Severino, Carmen Falcone.
      Astrocytes play essential roles in neuropathology. Human astrocytes exhibit unique properties, highlighting the importance of studying astrocytic responses in human models. Varicose projection astrocytes, previously considered exclusive to hominoids and a physiological type of astrocytes, were suggested to reflect pathological burden, albeit direct evidence linking them to neurological diseases has been lacking. Here, we demonstrate that varicose projection astrocytes also appear in other mammals and show, from four distinct human-based disease models, that varicose projection astrocytes are induced by neuroinflammation and characterized by distinctive subcellular features, indicating involvement in cellular stress responses, and their density is increased in aging and human neuropathology. Our findings establish varicose projection astrocytes as a reactive phenotype associated with neuropathology.
    DOI:  https://doi.org/10.1126/sciadv.ady8204
  28. Eur J Neurosci. 2026 Jul;64(2): e70637
    Short-Chain Fatty Acid-Dependent Neuroimmune Regulation in Autism Spectrum Disorder Pathogenesis.
    Arpan Dhungel, Rinchi Bora.
      Autism spectrum disorder manifests through dysbiosis across the microbiota-gut-brain-immune axis, characterized by depletion of short-chain fatty acid (SCFA)-producing taxa like Bifidobacterium, Faecalibacterium, and Roseburia, along with an increase in endotoxin-producing taxa like Desulfovibrio and Bacteroides. SCFA emerge as one of the regulators of neuroimmune homeostasis by governing microglial maturation through GPR43/GPR109A-dependent histone deacetylase inhibition, modulating astrocytic tryptophan-aryl hydrocarbon receptor signaling, and preserving tight junction integrity at blood-brain and blood-CSF barriers. SCFA insufficiency constitutes the upstream metabolic defect linking gut dysbiosis to ASD neuropathology, such as impaired microglial priming and brain-resident CD4+ T cell differentiation, reactive astrocytosis with kynurenine neurotoxicity superseding protective signaling, barrier breakdown enabling LPS-driven TLR4-NF-κB neuroinflammation, and excitatory/inhibitory imbalance from reduced glutamate decarboxylase and astrocyte glutamate dysregulation. This review advances an integrative SCFA-centric framework repositioning ASD as metabolite-dependent neuroimmune dysregulation during brain development. Preclinical and early clinical data demonstrate that SCFA restoration through prebiotic fiber/resistant starch, probiotics, or direct SCFA supplementation normalizes gastrointestinal symptoms, behavioral deficits, microglial morphology, and neurotransmitter ratios. This guides mechanistically targeted microbiota interventions with fecal/plasma SCFA profiling as stratification biomarkers, establishing precision therapeutic regimens for ASD.
    DOI:  https://doi.org/10.1111/ejn.70637
  29. bioRxiv. 2026 Jul 06. pii: 2026.07.03.736422. [Epub ahead of print]
    The Microglial Protein sTREM2 Inhibits the Bacterial Functional Amyloid CsgA and Suppresses Amyloid-Dependent Biofilm Formation.
    Anthony Balistreri, Mark Gomulinski, Matthew R Chapman, Jeffery W Kelly.
      Protein misfolding and aggregation, including amyloid fibril formation, underlie a large class of human diseases including prominent neurological disorders such as Alzheimer's and Parkinson's disease. A small number of human proteins have been identified that inhibit amyloidogenesis. One such protein is sTREM2, a soluble receptor liberated from microglia, the resident macrophages of the central nervous system. The extracellular domain of TREM2 is shed upon proteolytic cleavage to create sTREM2, which has previously been shown to inhibit amyloid-β aggregation in vitro . TREM2 is also expressed by intestinal macrophages, which are known to directly bind the bacterial amyloid curli and mount cytokine responses upon exposure. Here we show that sTREM2 is a sub-stoichiometric inhibitor of CsgA amyloidogenesis, CsgA being the major protein component of curli that drives biofilm formation in uropathogenic Escherichia coli and many other proteobacteria. In vitro , sTREM2 potently and sub-stoichiometrically inhibited CsgA amyloidogenesis in a dose-dependent manner. Kinetic modeling indicated that sTREM2 slowed primary and secondary nucleation, rather than altering fiber elongation. When added exogenously to bacterial growth medium, sTREM2 significantly suppressed curli-dependent pellicle biofilm formation without affecting bacterial growth. These findings establish sTREM2 as a member of the small group of human proteins capable of inhibiting bacterial functional amyloidogenesis, suggesting that gut-resident TREM2-expressing macrophages, which are already known to interact with curli, may employ sTREM2 as a physiologically relevant defense against bacterial amyloid formation.
    DOI:  https://doi.org/10.64898/2026.07.03.736422
  30. Immunol Res. 2026 Jul 17. pii: 72. [Epub ahead of print]74(1):
    Decoding the PI3K/Akt/mTOR-JAK/STAT signaling axis in multiple sclerosis: mechanistic crosstalk and therapeutic opportunities.
    Chandrayee Banerjee, Rohit Kumar Singh, Divya Choudhary, Md Nasiruddin Khan, Pankaj Kumar Maurya, Zuber Khan, Sidharth Mehan, Rajaram Samant, Manoj Tongra.
      Multiple Sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder characterized by demyelination, axonal injury, and progressive neurological dysfunction. Emerging evidence identifies the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways as interconnected regulators of neuroinflammation and immune dysregulation in MS. This review critically examines the mechanistic crosstalk between these signaling networks and their contribution to disease progression. Dysregulated PI3K/Akt/mTOR signaling influences T-cell activation, immunometabolic reprogramming, autophagy, and oligodendrocyte survival, whereas aberrant activation of the JAK2/STAT3 axis promotes Th17-cell differentiation, cytokine amplification, and sustained inflammatory responses within the central nervous system. Importantly, convergence between Th17/STAT3 signaling and PI3K/Akt-mediated metabolic pathways establishes a regulatory network that enhances microglial activation, blood-brain barrier disruption, and neuronal injury. The review further highlights the context-dependent role of mTOR signaling, which may simultaneously support remyelination and oligodendrocyte maturation while contributing to neurodegeneration when excessively activated. In addition to immune-cell-mediated mechanisms, emerging evidence demonstrates critical contributions of neuronal, glial, endothelial, and oligodendrocyte precursor cell signaling to MS pathology. Preclinical and clinical findings indicate that pharmacological modulation of these pathways can attenuate inflammatory responses and improve neuroprotection; however, therapeutic translation remains challenging because of their dual physiological and pathological functions. Collectively, this review provides an integrated perspective on PI3K/Akt/mTOR-JAK/STAT signaling interactions and highlights cell-specific molecular targets that may facilitate the development of more precise therapeutic strategies for MS.
    Keywords:  Immune dysregulation; JAK/STAT signaling pathway; Multiple sclerosis; Neuroinflammation; PI3K/Akt/mTOR signaling pathway; Therapeutic targets
    DOI:  https://doi.org/10.1007/s12026-026-09808-9
  31. Nat Commun. 2026 Jul 17.
    ASB2 inhibits lipid accumulation to promote ILC1 homeostatic fitness and anti-tumor immunity in the mouse liver.
    Boqun Bao, Xianwei Wang, Yawen Chen, Xiaodong Zheng, Yongyan Chen, Haoyu Sun, Guoliang Cui, Rui Sun, Zhigang Tian, Hui Peng.
      Type 1 innate lymphoid cells (ILC1) are abundant in the adult liver and are pivotal for immune surveillance and modulation, but the regulation of their maintenance and functionality remains underexplored. Here, we re-analyze published single-cell RNA- sequencing data and find increased expression of Asb2 in ILC1s from adult mouse livers. Conditional ablation of Asb2 in NKp46+ cells, depleting ASB2 in ILC1s and NK cells, in mice impairs ILC1 survival and reduces adult liver ILC1 numbers. Proteomics and bulk RNA-sequencing reveal enriched lipid metabolism pathways in ASB2-deficient ILC1s, concomitant with increased lipid storage. Importantly, pharmacological inhibition of lipid synthesis prevents the apoptosis of ASB2-deficient ILC1s in vitro. In a mouse model of colorectal cancer liver metastasis, we find increased ILC1 lipid storage, and conditional Asb2 deficiency in ILC1 cells exacerbates liver metastasis progression. Conversely, inhibiting lipid accumulation in wild-type colorectal cancer-bearing mice prolongs animal survival, potentially via promoting ILC1-mediated anti-tumor immunity. Thus, our study uncovers ASB2-regulated lipid metabolism as a gatekeeper for ILC1 homeostatic fitness and tumor surveillance, highlighting potential ILC1-based therapeutic strategies against liver tumors.
    DOI:  https://doi.org/10.1038/s41467-026-75517-4
  32. J Neuroinflammation. 2026 Jul 16.
    FPR2 deficiency alleviates LPS-induced depressive-like behaviors in mice by suppressing the microglial CSF1/NLRP3 inflammasome pathway.
    Hanqi Wang, Yijun Chen, Junna Chang, Zhen Liu, Yang Yu.
      Depression is one of the most prevalent psychiatric disorders worldwide, yet its pathogenesis remains unclear. Here, we aimed to investigate the effects of formyl peptide receptor 2 (FPR2), a key regulator of innate immunity and inflammation, on lipopolysaccharide (LPS)-induced depression-related behaviors in mice after intraperitoneal administration, and to elucidate its regulatory mechanisms in microglia. FPR2 knockout (Fpr2-/-) significantly attenuated LPS-induced depressive and anxiety-like behaviors in mice. LPS markedly increased FPR2 expression in microglia of the prefrontal cortex (PFC) and hippocampus, while only a minimal increase was observed in neurons. FPR2 deficiency alleviated LPS-induced microglial activation and reduced neuronal synaptic alterations. RNA sequencing and validation experiments confirmed that FPR2 deletion substantially decreased LPS-induced microglial NLRP3 inflammasome activation and IL-1β levels in the brain. Mechanistically, FPR2 regulated downstream NLRP3 activation by modulating CSF1, and FPR2/CSF1 activation was governed by its upstream ligand, serum amyloid A (SAA). Analysis of public clinical datasets revealed that SAA1 levels were significantly upregulated in the orbital ventral PFC of patients with major depressive disorder (MDD) and in the plasma of patients with late-life depression. These findings demonstrate that the SAA/FPR2/CSF1/NLRP3 pathway mediates LPS-induced depressive-like behaviors by regulating microglial activation and neuroinflammation.
    Keywords:  Anxiety; Colony-stimulating factor 1 (CSF1); Depression; Formyl peptide receptor 2 (FPR2); Lipopolysaccharide (LPS); Microglia; NOD-like receptor protein 3 (NLRP3); Neuroinflammation; RNA sequencing; Serum amyloid A (SAA)
    DOI:  https://doi.org/10.1186/s12974-026-03963-4
  33. Brain Commun. 2026 ;8(4): fcag257
    Neuroplasticity and immune system are related to altered grey matter networks: a cohort study in sporadic Alzheimer's disease.
    Diederick M de Leeuw, Flora H Duits, Ellen Dicks, Eleonora M Vromen, Charlotte E Teunissen, Frederik Barkhof, Wiesje M van der Flier, Pieter Jelle Visser, Betty M Tijms.
      Grey matter network topology is altered in Alzheimer's disease and these alterations are related to cognitive decline. Understanding the biological underpinnings of loss of brain connectivity may provide insights into mechanisms related to developing Alzheimer's dementia (i.e. dementia A+). We investigated which biological processes as measured in CSF proteomics were associated with loss of brain connections across the Alzheimer's disease continuum. We included 347 individuals with abnormal CSF amyloid [mean age ± standard deviation (SD) 66 ± 8; 98 cognitively unimpaired-A+, 88 mild cognitive impairment-A+, 161 dementia A+] and 146 cognitively unimpaired individuals with normal CSF amyloid (mean age ± SD 62 ± 8) and available T1w MRI-scans and CSF proteomic data (3097 proteins using tandem mass tag spectrometry) from the Amsterdam Dementia Cohort. We used an automated pipeline to construct grey matter networks from 3D-T1 sequences and for each network, calculated the small-worldness coefficient, which we previously found to be robustly related to cognitive decline. Linear models were applied to test associations between CSF protein levels and connectivity measures using an interaction term for clinical stage while controlling for connectivity density, age and sex. We validated our results in data from the Alzheimer's disease Neuroimaging Initiative (ADNI). Pathway enrichment analysis was performed for proteins associated with loss of brain connectivity (P < 0.05) using the Gene Ontology database. Individuals across the Alzheimer's disease continuum had lower small-worldness coefficients compared with controls (ANOVA P < 0.001). In amyloid positive individuals, higher levels of 222 proteins and lower levels of 482 proteins were associated with lower small-worldness coefficients and were enriched for innate immune system and neuroplasticity pathways, respectively. Stratified for disease stage, most protein associations with lower small-worldness coefficients were found in mild cognitive impairment A+ (n = 527 proteins) and dementia A+ (n = 799 proteins) with considerable overlap (n = 239 proteins). Proteins in these stages were enriched for complement activation and synaptic integrity. In cognitive unimpairment A+, we found proteins enriched for processes involved in apoptosis. We did not find any enriched biological processes in controls. Repeating analyses in ADNI indicated that similar biological processes were associated with altered grey matter network connectivity. Higher CSF levels of proteins involved in immune responses and lower levels of proteins related to neuroplasticity were associated with lower small-worldness coefficients across the Alzheimer's disease continuum. This suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to amyloid and tau.
    Keywords:  Alzheimer’s disease; CSF proteomics; grey matter networks
    DOI:  https://doi.org/10.1093/braincomms/fcag257
  34. Mol Neurodegener. 2026 Jul 17.
    The complex lipidome as a driver of tissue-specific pathology in adrenoleukodystrophy.
    Stephan Kemp, Marc Engelen, Yorrick R J Jaspers.
      X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, encoding a peroxisomal membrane transporter required for the import of very-long-chain fatty acids (VLCFA) into peroxisomes for degradation. ABCD1 deficiency leads to VLCFA accumulation in plasma and tissues. The resulting disease has a highly variable clinical presentation. In males, this manifests as cerebral demyelination, progressive myelopathy, and adrenal insufficiency, alone or in combination. Women predominantly develop myelopathy, while cerebral disease and adrenal insufficiency are rare, occurring almost exclusively in cases of extreme X-inactivation skewing toward the mutant allele. The lipid-mediated mechanisms linking VLCFA accumulation to tissue-specific pathology remain incompletely understood. Here, we review evidence that VLCFA-containing complex lipids, rather than free VLCFAs alone, are central mediators of tissue-specific pathology in ALD and discuss the therapeutic implications of this lipid-centric perspective. VLCFAs are incorporated into a broad range of complex lipids, including phosphatidylcholines, lysophosphatidylcholines, cholesterol esters, triacylglycerols, sphingomyelins, ceramides, and plasmalogens. The degree of lipid dysregulation increases with acyl chain length and saturation. VLCFA-containing lipid species correlate with disease severity across all clinical phenotypes. In the brain, VLCFA-containing phosphatidylcholines accumulate before demyelination onset, cholesterol ester accumulation is associated with neuroinflammatory cascades, and plasmalogen depletion reflects early oxidative damage. In the spinal cord, VLCFA-containing myelin lipids are associated with non-inflammatory axonopathy, mitochondrial dysfunction, and microglial phagocytic activation. In the adrenal gland, VLCFA accumulation in cholesterol ester-rich lipid droplets impairs ACTH receptor signaling and sequesters cholesterol from steroidogenic pathways. Enzymatic regulators of VLCFA homeostasis, including ELOVL1, SCD1, and the omega-oxidation enzymes CYP4F2 and CYP4F3B, are potential therapeutic targets for substrate reduction. Plasma VLCFA-lipid profiles correlate with disease severity across all affected tissues, positioning lipidomic profiling as a potential clinical instrument for risk stratification and treatment monitoring. Secondary lipid mediators amplify primary VLCFA toxicity through distinct, cell-type-specific pathways. The near-exclusive occurrence of cerebral ALD and adrenal insufficiency in women with extreme X-inactivation skewing suggests that partial reduction of the VLCFA lipid burden, rather than complete normalization, may be sufficient to prevent severe disease manifestations. This has direct implications for substrate-reduction therapy development.
    Keywords:  Adrenal insufficiency; ELOVL1; Leukodystrophy; Lipidomics; Lysophosphatidylcholine; Myelopathy; Neuroinflammation; Substrate reduction therapy; Very-long-chain fatty acids; X-linked adrenoleukodystrophy
    DOI:  https://doi.org/10.1186/s13024-026-00975-9
  35. Immunity. 2026 Jul 17. pii: S1074-7613(26)00271-2. [Epub ahead of print]
    Autophagy maintains high endothelial venule identity and function during inflammation.
    Kathryn A Jacobs, Yichao Hua, Apostolos Panagiotis Nikolakopoulos, Swati Gupta, Gerlanda Vella, Ana Filipa Domingues Laranjeiro, Julie Bonnereau, Mélanie Guyot, Maria Livia Sassano, Larissa Mourao, Feyza Cansiz, Gabriele Allies, Nicolas Van Baren, Sophie Lucas, Hiroto Kawashima, Wiebke Sondermann, Florian Rambow, Alpaslan Tasdogan, Colinda Scheele, Patrizia Agostinis, Gabriele Bergers.
      High endothelial venules (HEVs) play a crucial role in adaptive immune responses in secondary lymphoid organs (SLOs). They are equipped with high amounts of peripheral node addressin (PNAd), harboring carbohydrate structures that serve as L-selectin ligands to efficiently facilitate lymphocyte homing. During inflammation, the HEV network expands in SLOs, increasing lymphocyte infiltration, but the underlying mechanisms that maintain HEVs remain underexplored. Here, we report that autophagy is essential for HEV function and expansion. Using single-cell transcriptomics, unbiased proteomics, intravital imaging, and an inducible HEV tracer system in mice, we demonstrate that autophagy deficiency compromises lymphotoxin beta receptor (LTβR) signaling and the unfolded protein response in HEVs, leading to disrupted PNAd production, dedifferentiation, and reduced lymphocyte homing. Autophagy deficiency and LTβR blockade impair HEV function and reduce skin inflammation in psoriasis-affected mice by limiting immune infiltration and cytokine release. Our work reveals that autophagy safeguards HEV identity and function during inflammation.
    Keywords:  HEV; UPR; autophagy; high endothelial venules; inflammation; lymph node; lymphotoxin-beta receptor; peripheral node addressin; psoriasis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.020
  36. Signal Transduct Target Ther. 2026 Jul 15. pii: 284. [Epub ahead of print]11(1):
    Targeting the microglial phosphatidylethanolamine synthesis pathway promotes GABARAP-associated phagocytosis and Aβ clearance in Alzheimer's disease.
    Seung Jae Hyeon, Seung Chan Kim, Jiyeon Chu, Yeonseo Kim, Chaebin Kim, Uiyeol Park, Zahid Tufail, Phuong Thi Thanh Nguyen, Ahreum Eom, Sojung Kim, Yeyun Kim, Eunkyung Lee, Suhyun Kim, Seung Eun Lee, Jiwan Woo, Jin-A Lee, Kyung Eun Lee, Thor D Stein, Hyunbeom Lee, Junghee Lee, Hoon Ryu.
      Alzheimer's disease (AD) is a major cause of dementia and a prevalent age-related neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. Although metabolic activation or dysfunction of microglia is implicated in AD pathogenesis, the phospholipid metabolism-associated signaling mechanisms within microglia remain poorly defined. In this study, we demonstrate that quinolinic acid (QA), a byproduct of tryptophan catabolism via the kynurenine pathway, activates the microglial Kennedy pathway-responsible for de novo phosphatidylethanolamine (PE) biosynthesis-by upregulating the enzymes EPT1 and ETNK1. This activation markedly enhances the synthesis of PE species enriched in polyunsaturated fatty acids. Concurrently, QA significantly increases the expression of gamma-aminobutyric acid receptor-associated protein (GABARAP), promotes its lipidation, and facilitates the GABARAP-associated phagocytosis (GAP) of Aβ oligomers by microglia. Knockdown of EPT1 and ETNK1 attenuated QA-induced PE synthesis and impaired the GAP of Aβ oligomers, whereas inhibition of GABARAP lipidation via STBD1 deconjugase substantially reduced QA-mediated GAP. QA administration upregulated microglial Gabarap expression and decreased the Aβ plaque burden in the hippocampus of AD (5xFAD) mice, whereas Gabarap knockdown abrogated QA-induced microglial clearance of Aβ. Collectively, these findings reveal a paradoxically beneficial role of QA in activating a microglia-specific signaling cascade that promotes PE biosynthesis and GAP, thereby enhancing Aβ clearance and mitigating AD pathology. Targeting the microglial PE synthesis pathway and GAP may represent a promising therapeutic strategy to ameliorate Aβ accumulation and slow AD progression.
    DOI:  https://doi.org/10.1038/s41392-026-02789-z
  37. J Neuroinflammation. 2026 Jul 17.
    A BRD4/p300/SP1 epigenetic cascade drives microglial P2X4R transcription and promotes neuropathic pain.
    Daojuan Wang, Tingyu Wang, Yin Li, Xinye Yu, Shenquan Cai, Chun Wang, Yihan Wang, Zhengquan Zhu, Ying Huang, Yong Wang, Wangsen Cao, Gaojian Tao.
      Persistent upregulation of the purinergic receptor P2X4R is strongly associated with microglial activation in neuropathic pain, yet the epigenetic mechanisms linking chromatin remodeling to its dysregulation remain unclear. Here, we delineate a hierarchical epigenetic cascade that promotes transcriptional activation of P2X4R in spinal microglia following nerve injury. In a mouse spared nerve injury (SNI) model, microglial activation was accompanied by increased expression of P2X4R and the histone acetyltransferase p300, together with enhanced histone acetylation (H3K9ac, H3K27ac, H4K5ac, and H4K8ac) and increased chromatin accessibility at the P2rx4 promoter. Microglia-specific deletion of p300 blunted injury-induced histone acetylation and suppressed P2X4R upregulation. We further demonstrate that the acetylation reader BRD4 is recruited to these regions and cooperates with the transcription factor SP1 to drive P2rx4 transcription, supported by chromatin analyses revealing inducible assembly of a BRD4-p300-SP1 axis. Disruption of this cascade via p300 inhibition (C646) or BRD4 blockade (JQ1) attenuated spinal neuroinflammation and alleviated nociceptive hypersensitivity. Notably, reactivation of P2X4R by BzATP largely reversed the analgesic effects of BRD4 inhibition, establishing P2X4R as a critical downstream effector. Collectively, these findings support a p300-BRD4-SP1 epigenetic cascade linking chromatin remodeling to microglia-mediated neuropathic pain, highlighting this pathway as a potential therapeutic target.
    Keywords:  BRD4; Histone acetylation; Microglia activation; Neuropathic pain; P2X4R; P300
    DOI:  https://doi.org/10.1186/s12974-026-03965-2
  38. Brain. 2026 Jul 14. pii: awag147. [Epub ahead of print]
    CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.
    Hugh J Delaney, Sadia Islam, Dáire Healy, Ross Oglesby, Meghamsh Konda, Gudo M Rietman, Rebecca Lynch, Arshed Nazmi, James T Murray, Mark O Cunningham, Colm Cunningham.
      Alzheimer's Disease is the most common neurodegenerative disease worldwide, but significant gaps in pathophysiological understanding have hampered development of disease-modifying therapies. In Alzheimer's disease, neurophysiological function is impaired, with gamma frequency oscillations - thought to be essential for higher-order cognitive processes - disrupted in both patients and animal models. However, the mechanisms driving these disruptions are unclear and, in particular, the role of neuroinflammation in these changes is poorly understood. In this study, we investigated neuronal network dynamics in acute brain slices from APP/PS1 transgenic mice. Gamma frequency oscillations had significantly reduced amplitude in APP/PS1 brain slices at 9-11 months, accompanied by an increase in beta frequency power and heightened epileptiform activity. This is suggestive of a slowing in neuronal oscillations, considered a neurophysiological hallmark of Alzheimer's disease. Immunohistochemical analysis revealed a reduction in parvalbumin- and somatostatin-positive inhibitory interneuron populations. Treatment with gabazine demonstrated increased network sensitivity to GABAA receptor antagonism, further indicating compromised inhibitory control in APP/PS1. As these altered oscillatory dynamics correlated with microglial reactivity, we hypothesised a causal role for microglia. Administration of the CSF1R inhibitor GW2580 reduced microglial proliferation, attenuated development of the disease-associated microglial phenotype and partially rescued synaptic loss; but, had no significant impact on amyloid plaque burden or cognitive deficits. Unexpectedly, GW2580 treatment exacerbated neuronal network hyperactivity and the incidence and complexity of epileptiform activity. Microglia in GW2580-treated mice showed reduced CD68 expression and decreased engulfment of synaptic elements, potentially facilitating the persistence of hyperexcitable synapses. These findings support a role of microglia in regulating neuronal network homeostasis and caution against indiscriminate suppression of microglial activity in Alzheimer's disease. Therapeutic strategies targeting microglia must account for their homeostatic functions to avoid adverse effects on neuronal network stability.
    Keywords:  Alzheimer’s disease; CSF1R inhibition; gamma oscillations; microglia; neuronal network hyperexcitability; synaptic pruning
    DOI:  https://doi.org/10.1093/brain/awag147
  39. Neuromolecular Med. 2026 Jul 17. pii: 42. [Epub ahead of print]28(1):
    STAT6 Targets the Autophagy Pathway to Regulate Microglial Senescence in Cognitive Impairment Caused by Cerebral Small-Vessel Disease.
    Xiaolu Liu, Qing Liu, Jingwen Yang, Xia Hu, Xiaoqiu Zhu, Zhan Zhang, You Zuo, Jialin Huang, Lele Wu, Yuhua Fan, Yamei Tang, Zhongshan Shi.
      Cerebral small-vessel disease (CSVD) represents a major etiology of vascular cognitive impairment (VCI), driven by pathological processes such as cellular senescence and neuroinflammation. Among these, microglia-the brain's specialized immune cells-play a key role in driving neuroinflammation through their senescence, thereby exacerbating cognitive dysfunction. Although signal transducer and activator of transcription 6 (STAT6) activation has been implicated in alleviating neuroinflammation and cognitive deficits in CSVD, the underlying mechanisms remain unclear. This study sought to elucidate the roles of STAT6 and autophagy in the process of microglial senescence induced by CSVD. Using stroke-prone renovascular hypertensive rats (RHRSP) and chronic hypoxia-treated BV2 cells to assess cognitive function, microglial senescence, and autophagy, we observed that phosphorylation-mediated STAT6 activation significantly suppressed microglial senescence. Mechanistically, we found that phosphorylated STAT6 (pSTAT6) enhanced autophagy, which reduced the burden of senescent microglia and thereby ameliorated CSVD-induced VCI. These findings provide insights into the potential of targeting the STAT6 pathway in VCI associated with CSVD.
    Keywords:  Autophagy; Cerebral small-vessel disease; Cognitive impairment; Microglial senescence; STAT6
    DOI:  https://doi.org/10.1007/s12017-026-08944-7
  40. Alzheimers Dement. 2026 Jul;22(7): e71631
    Early Alzheimer´s disease blood biomarkers are associated with a higher risk for postoperative long-term cognitive decline: Insights from the FINDERI study.
    FINDERI investigators
       BACKGROUND: The study aim is to investigate whether blood biomarkers (BBMs) of Alzheimer's disease (AD) pathology are associated with postoperative cognitive dysfunction (POCD) after cardiac surgery.
    METHODS: Cognitive performance was assessed before and 12 months postoperatively using the Montreal Cognitive Assessment (MoCA) and categorized into stages-minimal (1), notable (2), and substantial (3) decline-in the FIND DElirium RIsk factors (FINDERI) study of patients undergoing cardiac surgery. BBMs were measured preoperatively (amyloid beta [Aβ]1-42, Aβ1-40, phosphorylated tau 181 [p-tau181], p-tau217, apolipoprotein E ε4 [apoE4] and apoE).
    RESULTS: A total of 394 patients completed follow-up investigations. POCD Stage 1 was observed in 105 (26.6%), POCD Stage 2 in 52 patients (13.2%), and POCD Stage 3 in 30 patients (7.6%). The AT217term (ratio Aβ1-40/1-42 * p-tau217) was significantly associated with POCD stages in multiple logistic regression.
    DISCUSSION: Early Alzheimer's BBMs are associated with POCD in patients, suggesting that our exploratory findings assessing BBMs may support risk stratification, inform decision-making, and contribute to strategies aimed at preventing POCD.
    Keywords:  Alzheimer´s disease; blood biomarker; postoperative cognitive dysfunction
    DOI:  https://doi.org/10.1002/alz.71631
  41. FASEB J. 2026 Jul 31. 40(14): e72141
    Metabolic Reprogramming of Macrophages Plays a Dual Role in Periodontitis: From Pathogenesis to Therapy.
    Tao Chen, Hongyu Ming, Junning He, Feng Zhou, Dongyang Wang, Fuwei Bai, Tongfeng Fang, Yi Man, Yingying Wu.
      The pathogenesis of periodontitis is closely intertwined with a complex immune and inflammatory cascade initiated by a dysbiotic dental biofilm. As key regulators of both innate and adaptive immunity, macrophages play a central role in the development and progression of periodontitis. Recent advances in immunometabolism have underscored the significance of metabolic reprogramming in shaping macrophage immune responses and influencing inflammation progression. In this review, we discuss the metabolic reprogramming of macrophages in glucose, lipid, and amino acid metabolism during periodontitis, as well as its intercellular consequences within the periodontal microenvironment. Moreover, we discuss how periodontal inflammatory microenvironmental factors drive this metabolic reprogramming, establishing a bidirectional, self-perpetuating vicious cycle. Finally, we highlight the therapeutic potential of targeting macrophage metabolism and emphasize the dual role of metabolic reprogramming as both a driver of periodontitis progression and a potentially reversible process that can be therapeutically redirected.
    Keywords:  immunometabolism; macrophage; metabolic reprogramming; pathogenesis; periodontitis; therapy
    DOI:  https://doi.org/10.1096/fj.202600558RRR
  42. bioRxiv. 2026 Jul 11. pii: 2026.07.07.736860. [Epub ahead of print]
    APOE4 genotype and old age interact to impact cerebrovascular function, brain volume, and neuroinflammation in mice.
    Mackenzie N Kehmeier, Young D Choi, Abigail E Cullen, Benjamin Zimmerman, Thomas Leonhardt, Maddie Snyder, Tucker Cleveland, Naly Setthavongsack, Randall L Woltjer, Martin M Pike, Nabil J Alkayed, Ashley E Walker.
      Old age and the apolipoprotein E ε4 ( APOE4) genotype are two of the greatest risk factors for late-onset Alzheimer's disease (LOAD). However, the interaction between these is poorly understood, as most preclinical studies use young mice. Therefore, we assessed the interaction between APOE genotype and age across a comprehensive set of cerebrovascular and related outcomes. We performed in vivo imaging, ex vivo cerebral artery studies, behavioral tests, and molecular analyses in male and female homozygous APOE3 and APOE4 mice at ∼6 months (young) and ∼24 months (old). APOE4 interacted with old age to lead to deficits in brain volume and greater microglia content. Old APOE4 mice also exhibited greater cerebral artery vasoconstriction to endothelin-1 (ET-1) than old APOE3 mice, a response concomitant with age-and genotype-related differences in the expression of ET-1 receptors and endothelin-converting enzyme. While we found several interactions between age and APOE genotype, only age impacted cognitive function, cerebral artery endothelial function, and arterial stiffness. In summary, we found that brain volume, neuroinflammation, and ET-1-related outcomes were influenced by the interaction of APOE genotype and age, while other outcomes were affected only by age. As such, an altered ET-1 response and greater neuroinflammation may contribute to the increased risk for LOAD in APOE4 carriers.
    DOI:  https://doi.org/10.64898/2026.07.07.736860
  43. Sci Adv. 2026 Jul 17. 12(29): eadz8681
    Iron overload suppresses LKB1 and induces IL36G anti-tumor immunity in PDAC metastasis.
    Douglas E Biancur, Harsha Venkatesh, Amy Crawford, Yealeen Jeong, Albert S W Sohn, Kevin S Kapner, Keisuke Yamamoto, Elaine Y Lin, Robert S Banh, Mohamad Assi, Beny Shapiro, Peter Yu, Soomin C Song, William A Coetzee, Andrew J Aguirre, Alisha N Jones, Alec C Kimmelman, Richard Possemato.
      Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency - loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor Stk11 (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5'-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to Il36g mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5'UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.
    DOI:  https://doi.org/10.1126/sciadv.adz8681
  44. Science. 2026 Jul 16. 393(6808): eady1678
    Dendritic cells control tertiary lymphoid structure development and maintenance in cancer.
    Raphaël Mattiuz, Jesse Boumelha, Emmanouil Aerakis, Jessica Le Berichel, Pauline Hamon, Laszlo Halasz, Abishek Vaidya, Brian Y Soong, Emir Radkevich, Hye Mi Kim, Matthew D Park, Romain Donne, Leanna Troncoso, Rachel A Kaplan, Clotilde Hennequin, Isaias Hernández-Verdin, Lucía López, Frederika Rentzeperis, Darwin D'Souza, Medard Ernest Kaiza, Ian P MacFawn, Meriem Belabed, Guillaume Mestrallet, Etienne Humblin, Raphaël Merand, Samarth Hegde, Jean-Christophe Lone, Giorgio Ioannou, Sinem Ozbey, Igor Figueiredo, Alexander Tepper, Hajer Merarda, Nadine Serhan, Maximilian M Schaefer, Jinping An, Ray A Ohara, Erika Nemeth, Simon Goldstein, Amanda M Reid, Moataz Noureddine, Alexandra Tabachnikova, Giulia Maria Piperno, Maria Tsoumakidou, Jalal Ahmed, Alexandros D Polydorides, Nina Bhardwaj, Amaia Lujambio, Zhihong Chen, Edgar Gonzalez Kozlova, Seunghee Kim-Schulze, Joshua D Brody, Michael Schotsaert, Christine Moussion, Sacha Gnjatic, Vladimir Roudko, Florent Ginhoux, Kenneth M Murphy, Catherine Sautès-Fridman, Wolf Herman Fridman, Brian D Brown, Thomas U Marron, Federica Benvenuti, Jason G Cyster, Hélène Salmon, Tullia C Bruno, Nikhil S Joshi, Alice O Kamphorst, Miriam Merad.
      Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7+ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non-small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)-driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1-major histocompatibility complex class 1 (MHC-I) and -MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (TFH) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.
    DOI:  https://doi.org/10.1126/science.ady1678
  45. Pharmacol Res. 2026 Jul 11. pii: S1043-6618(26)00254-9. [Epub ahead of print]231 108339
    Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy.
    Yunzhi Shang, Zhiyong Zhai, Lin Cong, Xiaoyu Dong.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing global health challenge. Despite decades of research dominated by the amyloid cascade hypothesis, single-target therapies aimed at Aβ or tau have largely failed, underscoring the need for a broader framework. Emerging evidence implicates neuroimmune dysfunction as a central driver of AD pathology, with the "peripheral-central immune axis" emerging as a critical node. The APOE4 allele, the strongest genetic risk factor for sporadic AD, plays a pivotal role in both central nervous system (CNS) lipid metabolism and peripheral immune homeostasis. This review synthesizes the association between APOE4 and peripheral immune dysregulation and its impact on neurodegeneration. We discuss APOE expression in CNS and peripheral immune cells, highlighting APOE4-associated alterations in monocyte/macrophage polarization, T cell subsets via IL-7/IL-7R downregulation, and gut microbiota composition. We delineate mechanisms by which APOE4 is associated with blood-brain barrier compromise, may promote conditions for immune cell trafficking, and contributes to neuroinflammation. Integrating preclinical and clinical evidence, we propose an "APOE4-associated peripheral-central immune infiltration cascade" as a unifying framework for understanding systemic AD pathogenesis. Finally, we review emerging therapeutic strategies targeting peripheral immunity and APOE, discussing multi-target approaches guided by APOE genotype and immune biomarkers, shifting from a CNS-centric toward a systemic immunomodulatory paradigm for precision medicine.
    Keywords:  APOE4; Alzheimer's disease; Immunotherapy; Neuroinflammation; Peripheral-central immune axis
    DOI:  https://doi.org/10.1016/j.phrs.2026.108339
  46. Neuroscience. 2026 Jul 17. pii: S0306-4522(26)00472-0. [Epub ahead of print]
    Air-Liquid interface midbrain organoids model the pathological features of Parkinson's disease.
    Sara Kälvälä, Polina Abushik, Mohammad Rezaie, Antonios Dougalis, Jari Koistinaho, Maria Gardberg, Kelvin C Luk, Tarja Malm, Anssi Pelkonen, Šárka Lehtonen.
      Human-induced pluripotent stem cell-derived midbrain organoids offer a promising platform for modeling Parkinson's disease (PD). Yet, their utility has been limited by the absence of microglia and the development of a necrotic core during maturation. Here, we present an air-liquid interface (ALI) slice culture system for extended cultivation of midbrain organoids (mORGs), enabling efficient microglial integration, improved neuronal viability, and enhanced functional maturation. Compared with conventional mORGs grown in suspension cultures, the ALI method supports more consistent engraftment of microglial progenitors and the development of astrocytes and oligodendrocyte progenitors, as revealed by single-cell RNA sequencing. Functionally, ALI-mORGs exhibited robust and reproducible neural network activity, with N-methyl-D-aspartate (NMDA) stimulation reliably inducing synchronous bursting, as measured by 3D microelectrode array recordings. Importantly, exposure to alpha-synuclein (αSyn) preformed fibrils triggered the progressive accumulation of phosphorylated αSyn inclusions, closely recapitulating key features of PD pathology. The ALI-mORG model addresses major limitations of existing systems and provides a more physiologically relevant platform for investigating cellular mechanisms of PD and for supporting future therapeutic strategies.
    Keywords:  Air-liquidinterface; Electrophysiology; Microglia; Midbrainorganoids; Parkinson’sdisease; hiPSCs
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.07.027
  47. bioRxiv. 2026 Jul 11. pii: 2026.07.11.737778. [Epub ahead of print]
    Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.
    Yohannes Ambaw, Alissa Nana, Li Zhuoning, Shubham Singh, Mara Monetti, Bruce L Miller, Salvatore Spina, Lea Tenenholz Grinberg, William W Seeley, Tobias C Walther, Robert Farese.
      Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick disease's, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.07.11.737778
  48. Alzheimers Dement (N Y). 2026 Jul-Sep;12(3):12(3): e70269
    Anti-amyloid nanobody-Fc fusion protein drives potent amyloid clearance through microglial recruitment.
    Zonghui Ding, Katelin A Gibson, David G Nascari, Lauren E Tallant, Samantha M Bouchal, Dennis W Dickson, John D Fryer.
       INTRODUCTION: Anti-amyloid beta (Aβ) monoclonal antibodies are effective at lowering amyloid in Alzheimer's disease (AD). However, whether Fc-mediated effector function is absolutely required for efficacy is not completely understood. This is important for optimizing therapeutic efficacy and mitigating side effects such as amyloid-related imaging abnormalities (ARIA). Antibodies lacking Fc effector function, like single-domain antibodies (nanobodies), offer a unique tool to dissect these mechanisms, as their small size facilitates blood-brain barrier (BBB) penetration and allows Fc-mediated functions to be studied independently.
    METHODS: We immunized a llama with Aβ aggregates and constructed a phage display library to screen for aggregate-specific nanobodies. Lead candidates were characterized by epitope mapping and binding affinity to amyloid plaques in both murine and human AD brain tissues. We further assessed their BBB permeability and evaluated their efficacy in clearing pre-existing plaques in amyloid precursor protein (APP)/presenilin 1 (PS1) mice.
    RESULTS: We identified two lead nanobodies, 3A11 and 2D10, that bind distinct epitopes and specifically bind Aβ plaques in murine and human AD brain tissues. Following systemic administration, the monovalent, unmodified (Fc-less) 2D10 nanobody, but not 3A11, successfully crossed the BBB and engaged amyloid plaques in APP/PS1 mice. However, despite robust target engagement, the Fc-less 2D10 failed to recruit microglia or reduce plaque burden. In contrast, an engineered 2D10-Fc fusion antibody potently cleared amyloid plaques, achieving a reduction in pathology comparable to aducanumab treatment. This efficacy was directly correlated with Fc-mediated microglial recruitment and activation, demonstrating that the Fc domain is essential for phagocytic plaque removal.
    DISCUSSION: Our findings demonstrate that Fc effector function is indispensable for microglial-mediated amyloid clearance in vivo. By clarifying this fundamental mechanism, this study provides a framework for the rational design of next-generation immunotherapies. Furthermore, 2D10-Fc represents a promising therapeutic candidate, combining the high-affinity targeting of nanobodies with the effector power necessary for robust plaque clearance.
    Keywords:  Alzheimer's disease; Fc effector function; amyloid plaques; blood–brain barrier; immunotherapy; microglia; nanobody; phagocytosis
    DOI:  https://doi.org/10.1002/trc2.70269
  49. Nat Commun. 2026 Jul 16.
    Analysis of gene co-expression connectivity dynamics implicates aberrant neuron-oligodendroglia interactions in schizophrenia.
    Eugenia Radulescu, Petra E Vértes, Shizhong Han, Jennifer A Erwin, Apuã C M Paquola, Thomas M Hyde, Joel E Kleinman, Tomoyo Sawada, Edward T Bullmore, Daniel R Weinberger.
      Dysconnectivity in schizophrenia is a pervasive concept across various levels of systems biology. To better understand disrupted patterns of molecular connectivity in schizophrenia, we apply innovative approaches to gene co-expression networks starting from multiple regions of postmortem brain (bulk RNA-Seq from dorso-lateral prefrontal cortex- (DLPFC) (Ndonors=297; sex: M/F = 212/85), hippocampus (Ndonors=250; sex: M/F = 181/69) and caudate (Ndonors=349; sex: M/F = 242/107). Here we identify differentially connected genes (DCG) in schizophrenia networks that deviate from architectural relationships characteristic of neurotypical gene networks based on three network metrics- total connectivity (kTot), clustering coefficient (C), and intra-module degree (kIn). We find multiple DCG consistent across all brain regions, most of which we then independently confirm in brain single nuclei (snRNAseq) data and in four independent human iPSC-derived brain organoids. DCG specific for each network parameter shows enrichment in schizophrenia genetic signal, in pathways prominently related to neurons and oligodendroglia functionality, and in cell-type specific co-expression patterns that differ between neurotypical and schizophrenia, implicating neuronal-oligodendroglia incoordination.
    DOI:  https://doi.org/10.1038/s41467-026-75470-2
  50. J Clin Invest. 2026 Jul 15. pii: e202262. [Epub ahead of print]136(14):
    Gut microbe-derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice.
    Fang R Zhao, Maksim Kleverov, Emma S Winkler, Russell B Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-Ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T Baldridge, Thaddeus S Stappenbeck, Larissa B Thackray, Chyi-Song Hsieh, Scott A Handley, Chun-Jun Guo, Michael A Fischbach, Maxim N Artyomov, Michael S Diamond.
      Oral antibiotics can predispose to joint inflammation, but this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short-chain fatty acids (SCFAs), greater intestinal permeability, and activation of gut-associated immune cells and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4+ T cells, and proinflammatory cytokines. Administration of exogenous SCFAs or colonization of mice with bacterial species that generate SCFAs mitigated CHIKV-induced joint inflammation. scRNA-seq revealed that gut-derived SCFAs ameliorate the inflammatory phenotype of synovial CD4+ T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.
    Keywords:  Adaptive immunity; Immunology; Infectious disease; Innate immunity; Microbiology
    DOI:  https://doi.org/10.1172/JCI202262
  51. Cell Rep. 2026 Jul 13. pii: S2211-1247(26)00724-2. [Epub ahead of print]45(7): 117646
    Medial entorhinal-hippocampal desynchronization parallels the emergence of memory impairment in a mouse model of Alzheimer's disease pathology.
    Lauren M Vetere, Angelina M Galas, Nick Vaughan, Cassidy Kohler, Yu Feng, Zoé Christenson Wick, Paul A Philipsberg, Olga Liobimova, Kathryn E Gordon, Antonio Fernandez-Ruiz, Denise J Cai, Tristan Shuman.
      Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive impairments in episodic and spatial memory, as well as circuit and network-level dysfunction. While functional impairments in medial entorhinal cortex (MEC) and hippocampus (HPC) have been observed in patients and rodent models of AD, it remains unclear how communication between these regions breaks down in disease, and what specific physiological changes are associated with the onset of memory impairment. Here, we use silicon probes to simultaneously record neural activity in MEC and HPC before or after the onset of spatial memory impairment in the 3xTg mouse model of AD pathology. We find that reduced hippocampal theta power, reduced MEC-CA1 theta coherence, and altered phase locking of MEC and hippocampal neurons all coincide with the emergence of spatial memory impairment in 3xTg mice. Together, these findings suggest that disrupted temporal coordination of neural activity in the MEC-hippocampal system parallels the emergence of memory impairment in a model of AD pathology.
    Keywords:  Alzheimer's disease; CP: Neuroscience; circuit desynchronization; electrophysiology; entorhinal cortex; hippocampus; learning and memory; phase-locking; theta oscillations
    DOI:  https://doi.org/10.1016/j.celrep.2026.117646
  52. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00027-9. [Epub ahead of print]187 281-330
    Metabolic reprogramming in Alzheimer's disease: Interaction between receptor tyrosine kinase signaling, noncoding RNAs, and Neuron-Glia energy networks.
    Ankita Karmakar, Puja Roycowdhury, Priyanka Sengupta, Debashis Mukhopadhyay.
      Alzheimer's disease (AD) is increasingly understood as a disorder involving impaired brain energy metabolism rather than being solely caused by amyloid and tau pathology. This chapter offers a comprehensive overview of how glucose hypometabolism, mitochondrial dysfunction, and disrupted neuron-astrocyte metabolic coupling collectively creates an "energy crisis" in vulnerable neuronal circuits. Early issues with glucose transport (GLUT1/3/4), reduced glycolytic flux, TCA cycle problems, and excessive mitochondrial fission all contribute to decreased ATP production and increased oxidative stress. Along with these metabolic disturbances, receptor tyrosine kinase (RTK) pathways-including insulin/IGF-1, TrkB/BDNF, FGFRs, and EGFR-lose their regulatory control, leading to insulin resistance, synaptic failure, and increased vulnerability to Aβ and tau toxicity. The chapter also highlights noncoding RNAs (miRNAs and lncRNAs) as key post-transcriptional regulators of metabolic and RTK signaling networks. Harmful miRNAs (such as miR-34a, miR-210-3p) suppress glycolytic enzymes and mitochondrial genes, while protective miRNAs (miR-23a/b, miR-455-3p, miR-195) decrease in AD. Metabolic lncRNAs, like EPB41L4A-AS1, decline with age and contribute to NAD⁺ depletion and bioenergetic imbalance. Recognizing the link between RTK dysregulation and ncRNA-driven metabolic control reveals new therapeutic possibilities to restore mitochondrial function, enhance neurotrophic support, and re-establish energy balance in the AD brain.
    Keywords:  Alzheimer’s disease; Metabolism; Mitochondrial dysfunction; NcRNA; RTK
    DOI:  https://doi.org/10.1016/bs.irn.2026.02.007
  53. Nat Commun. 2026 07 14. pii: 6188. [Epub ahead of print]17(1):
    Distinct molecular subgroups in pediatric and young-onset meningiomas require age-adapted risk stratification.
    Natalie Berghaus, Arnault Tauziède-Espariat, Thomas Hielscher, Dilan Savran, Daniel Schrimpf, Kirsten Göbel, Eric Stutheit-Zhao, Lukas Friedrich, Felix Keller, Fuat Kaan Aras, Filippo Nozzoli, Dominik Sturm, Christine L White, Simone Schmid, Christian Mawrin, Julia E Neumann, Till Acker, Rudi Beschorner, Christian Hartmann, Irem Saribiyik, Arda Inan, Ayça Erşen-Danyeli, Mariëtte E G Kranendonk, Sybren L N Maas, Eelke M Bos, Eleonora Aronica, Saskia M Peerdeman, Nikki B Thuijs, Angelika Mühlebner, Benno Kusters, Wilfred F A den Dunnen, Cinzia E Lavarino, Stéphanie Puget, Jason Chiang, Sonika Dahiya, Melike Pekmezci, Arie Perry, Oluwadamilola Akanji, Miriam Ratliff, Christel Herold-Mende, Sandro M Krieg, Wolfgang Wick, Stefan M Pfister, Pieter Wesseling, Andreas von Deimling, Pascale Varlet, Felix Sahm, Philipp Sievers.
      Meningiomas in pediatric and adolescent/young adult patients are poorly characterized biologically and clinically, and risk stratification is largely extrapolated from adult tumors. We analyze 293 tumors from patients aged 0-39 years using integrated histopathological and molecular profiling. Youth-onset meningiomas are enriched for NF2 and SMARCE1 alterations and exhibit a gain-dominated copy-number landscape, including recurrent chr17q gain, whereas canonical adult high-risk features, such as chr1p loss, lack prognostic significance. Adult-derived prognostic frameworks, including WHO grade, methylation-based stratification and integrated risk scores, fail to predict progression in patients ≤21 years of age. Tumors segregate into age-enriched epigenetic clusters defined by SMARCE1, NF2 and BAP1 alterations. Among NF2-altered tumors, patterns of Merlin inactivation, shaped by germline status and co-occurring copy-number variations, delineate biologically divergent subsets. In patients ≤21 years, extent of resection is the dominant predictor of outcome, while molecular features further refine risk assessment. These findings define pediatric and young adult meningiomas as a distinct molecular entity and support age-adapted risk refinement that integrates molecular features with strong clinical determinants.
    DOI:  https://doi.org/10.1038/s41467-026-75357-2
  54. J Cereb Blood Flow Metab. 2026 Jul 15. 271678X261471282
    EXPRESS: Single-Cell Analysis of Microglia and Monocyte Dynamics Uncovers Distinct TNF-driven Neuroimmune Signatures in Humans after Intracerebral Hemorrhage.
    Yuki Kawamura, Conor W Johnson, Jonathan DeLong, Lucas Paulo de Lima Camillo, Sofia E Velazquez, Munetomo Takahashi, Hannah E Beatty, Ryan Hebert, Branden J Cord, Charles Matouk, Mike Askenase, Lauren H Sansing.
      Innate immune cells contribute to both secondary brain injury and repair following intracerebral hemorrhage (ICH). However, the signaling pathways governing initial inflammatory and subsequent reparative myeloid programs in living patients remain poorly understood. To better characterize mononuclear phagocyte cell changes over time, we generated a single-cell transcriptomic dataset of paired hematoma clot evacuates and peripheral blood samples from 10 patients following ICH (5 - 290 hours). We identified distinct populations of activated and TNF-low microglia, as well as a highly activated population of CD14+ monocytes in the hematoma. Perturbation analysis identified TNF signaling as the primary driver of hematoma monocyte activation. Custom temporal trajectory analysis using single-cell foundation model embeddings found that this TNF response in monocytes was transient, peaking early after hemorrhage and decreasing over the following 48 hours as monocytes shifted to reparative transcriptional programs. Transiently activated microglia emerged as the likely acute source of TNF among analyzed populations, signaling through monocyte TNFR2. Surprisingly, acute TNF signaling in CD14+ monocytes was also associated with better severity-adjusted neurological outcomes both in our cohort and an independent validation cohort. These findings suggest acute TNF signaling between activated microglia and hematoma-associated monocytes, particularly through TNFR2, may contribute to recovery following ICH.
    DOI:  https://doi.org/10.1177/0271678X261471282
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