bims-micgli Biomed News
on Microglia
Issue of 2026–05–17
57 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
  2. α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
  3. Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.
  4. Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.
  5. Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota-butyrate-mTORC1-ISR relay along the gut-brain axis.
  6. Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination.
  7. Immune receptor LAG3 regulates microglia function during Alzheimer's disease.
  8. Cell-type-specific APOE4 cascade across the Alzheimer's disease continuum.
  9. Sustaining microglial reparative function enhances stroke recovery.
  10. SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
  11. Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states.
  12. Multimodal profiling of immune responses reveals innate-adaptive immune imbalance in human bornavirus encephalitis.
  13. Single-cell transcriptomic analysis reveals APOE genotype-dependent sex differences in Alzheimer's disease.
  14. Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.
  15. Microglial Plasticity in Vascular Dementia: Mechanisms and Therapeutic Reprogramming.
  16. IFI204 drives gasdermin D-mediated mitochondrial permeabilization to amplify neuronal pyroptosis in ischemic stroke.
  17. A CSF disease-associated macrophage signature defines progressive multiple sclerosis.
  18. Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer's disease.
  19. Early Müller Glial Activation and Retinal Ganglion Cell Synaptic Dysfunction in APP/PS1 Mice.
  20. Phagocytosis deficient glia display phagosome processing defects and macrophage recruitment to the brain of adult Drosophila melanogaster.
  21. miR‑223‑3p promotes microglial lactylation and M1 polarization via the FBXW7/Notch1/Hes1/SIRT1 axis.
  22. Inter-organ metabolic feedback via BCAA catabolism regulates glucagon-like hormone secretion in Drosophila.
  23. Somatic variants in microglia-like cells linked to Alzheimer's disease pathology.
  24. Microglia-specificity of different markers is overridden in glioblastoma specimens.
  25. CD8+ T cells turn resilient under stress.
  26. Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons.
  27. Serpine1 regulates Th17 cell differentiation and exacerbates IMQ-induced skin inflammation.
  28. Microglia Reprogramming in Glioblastoma: Stem Cell-Derived Factors as Emerging Immunomodulators.
  29. Amyloid Plaques Ameliorate Memory Deficits and Hippocampal Neuron Loss in an Aβ4-42-Driven Alzheimer's Disease Mouse Model.
  30. Growth charts reveal how the brain's 'communication highways' change throughout life.
  31. Sphingolipid regulation by yeast Mdm1 supports adaptive remodeling of the methionine transporter Mup1.
  32. ABL kinases regulate FGF signaling independent of CRK phosphorylation to prevent Peters anomaly type II.
  33. Deployment of endocytic machinery to periactive zones of nerve terminals is independent of active zone assembly and evoked release.
  34. Neuroinflammatory diseases triggered by cerebral hemorrhage: microglial iron accumulation and ferroptosis.
  35. Microglia in autism spectrum disorder: heterogeneity, immunometabolism, and synapse-related pathways.
  36. Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.
  37. Optics-free spatial genomics for mapping mammalian brain aging by IRISeq.
  38. Intrinsic endothelial remodeling drives brain capillary repair.
  39. PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer's disease model.
  40. Non-economic social deprivation and cognitive functioning later in life: Results from the DELCODE study.
  41. Investigation of the myelin-amyloid interplay in Alzheimer's disease: insights from novel dsCMA imaging in mouse and human brains.
  42. Cellular state heterogeneity underlying sex differences in Alzheimer's disease based on single-cell transcriptome.
  43. Frequency of mixed neuropathologies in individuals with down syndrome with and without Alzheimer's dementia.
  44. TREM2 promotes adipogenesis of PDGFR-α+ adipose stem cells but is dispensable for adipose remodeling and metabolic health during diet-induced obesity.
  45. Andrograpanin attenuates secondary neuroinflammation after spinal cord injury by modulating microglial glycolysis via HIF-1α.
  46. Microglia in Epilepsy: From Molecular Mechanism to Therapeutic Strategy.
  47. Endothelial cell-secreted SPARC suppresses astrocytic CD59 expression and promotes astrocytopathy in a mouse model of neuromyelitis optica spectrum disorders.
  48. Functional targeting of PTTG1 in pericytes restores vascular integrity in diabetic retina.
  49. Spatiotemporal control of PIWI compartmentalization by mitochondrial scaffolds defines pachytene piRNA pathway organization.
  50. Peripheral Metabolic Reprogramming Links TDP-43 Proteinopathy to Sleep Disruption.
  51. Metabolic control of neuronal redox homeostasis: implications of pentose phosphate pathway loss in the nervous system.
  52. Comparative Analysis of Mouse CSF Proteins in Experimental Autoimmune Encephalomyelitis Model and Cuprizone-Induced Demyelination Model by Olink Proteomics.
  53. In situ structure of the human gap junction.
  54. Mouse eyes photosynthesize after plant-to-animal transplant.
  55. Generation of spinal cord organoids from human induced pluripotent stem cells caudalised to a lumbar fate.
  56. Macrophages are dispensable for taste bud regeneration upon nerve injury repair.
  57. Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.
  1. Nat Commun. 2026 May 12.
    Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
    Davide Caredio, Giovanni Mariutti, Lisa Polzer, Beatrice Gatta, Martina Cerisoli, Yasmine Laimeche, Giulia Miracca, Jeanne Droux, Mohamad El Amki, Marc Emmenegger, Marian Hruska-Plochan, Susanne Wegener, Magdalini Polymenidou, Matthias Schmitz, Inga Zerr, Elena De Cecco, Adriano Aguzzi.
      Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.
    DOI:  https://doi.org/10.1038/s41467-026-73003-5
  2. Nat Commun. 2026 May 15.
    α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
    Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.
      Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While α-synuclein (α-Syn) aggregates are known to promote TNT formation, the underlying mechanisms remain poorly defined. Here, using human neuronal and microglial cell lines, as well as iPSC-derived dopaminergic neurons and microglia, we show that α-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS-STING-NF-κB-IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of α-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under α-Syn-induced stress also triggers a bystander inflammatory response in microglia, suggesting a neuroimmune activation. Our findings identify mitochondrial damage and STING-mediated inflammation as key drivers of TNT formation and α-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.
    DOI:  https://doi.org/10.1038/s41467-026-73136-7
  3. Neuron. 2026 May 12. pii: S0896-6273(26)00328-4. [Epub ahead of print]
    Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.
    Marc Carceles-Cordon, Eliza M Brody, Masen L Boucher, Michael D Gallagher, Robert T Skrinak, Travis L Unger, Cooper K Penner, Adama J Berndt, Sromona Das, Katie Lam, Rudolf Jaenisch, Vivianna Van Deerlin, Edward B Lee, Kurt Brunden, Kelvin C Luk, Alice S Chen-Plotkin.
      Glycoprotein nonmetastatic melanoma B (GPNMB) is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein in Parkinson's disease (PD). Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB can function in a non-cell-autonomous manner. In the human brain, GPNMB is widely expressed in neurons and microglia. In induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increase with exposure to apoptotic neurons. In the aSyn fibril-seeded model of PD, iMicroglia-derived GPNMB enhances neuronal aSyn uptake and development of aSyn pathology, including in GPNMB knockout neurons. Conversely, anti-GPNMB antibodies rescue neurons from developing aSyn pathology. Finally, in 1,675 human postmortem cases, GPNMB genotypes conferring higher GPNMB expression are associated with more widespread aSyn pathology. Our data suggest a positive feedback loop, where neurodegeneration triggers increased microglial GPNMB secretion, leading to increased neuronal aSyn pathology and neurodegeneration. Importantly, this cycle can be therapeutically interrupted by anti-GPNMB antibodies.
    Keywords:  GPNMB; Parkinson’s disease; aSyn; alpha-synuclein; anti-GPNMB antibody; microglia; neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.033
  4. J Neuroinflammation. 2026 May 12.
    Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.
    Xiaoyang Lu, Yiling Jiang, Xiuqing Lin, Yuanxing Zhang, Qin Liu, Shouwen Chen.
       BACKGROUND: Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.
    RESULTS: In this study, we demonstrate that PpSEVs efficiently penetrate the blood-brain barrier and show relative enrichment in the hippocampus CA3 region of 5×FAD mice. Transcriptomic profiling and functional assays reveal that PpSEVs reverse AD pathology by reconfiguring the dysregulated neuroimmune network rather than through broad immune suppression. Specifically, PpSEVs exert a dual-action effect on microglia by blocking caspase-1/GSDMD axis-mediated pyroptosis, while simultaneously enhancing CD68-dependent amyloid-β clearance. This microglial modulation occurs in tandem with the reprogramming of reactive astrocytes, characterized by the downregulation of neurotoxic C3 and the upregulation of neuroprotective S100A10. Furthermore, we identify a direct, glia-independent neurotrophic pathway in which PpSEVs activate neuronal BDNF signaling to rescue synaptic integrity and cognitive function.
    CONCLUSIONS: By demonstrating robust cross-species efficacy without provoking immunotoxicity, our study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.
    Keywords:  Alzheimer’s disease; Cross-species therapy; Microglia; Neuroinflammation; Porcine plasma; Reactive astrocyte; Small extracellular vesicles
    DOI:  https://doi.org/10.1186/s12974-026-03866-4
  5. J Neuroinflammation. 2026 May 13.
    Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota-butyrate-mTORC1-ISR relay along the gut-brain axis.
    Ming-Zhu Wang, Ze-Bang Du, Wen-Qi Xu, Yu-Han Xie, Lei-Lei Wang, Xin-Xin He, Yu-Han Wang, Han-Ying Zheng, You-Liang Yao, Ya-Bin Song, Zhong-Ning Lin, Yu-Chun Lin.
      Eco-friendly poly(butylene adipate-co-terephthalate) (PBAT) is widely marketed as biodegradable, yet the neurotoxicity of derived PBAT microplastics (PBAT-MPs) and their underlying mechanisms remain poorly characterized. Here we identify a previously unrecognized "gut microbiota-butyrate-neuro-lipid" axis linking intestinal PBAT-MPs exposure to hippocampal microglial lipotoxicity and cognitive impairment. By integrating fecal microbiota transplantation (FMT) with multi-omics analyses, we demonstrate that orally administered PBAT-MPs preferentially accumulate in the colon, impair epithelial barrier integrity, deplete butyrate-associated taxa, including Muribaculaceae and Alloprevotella, and enrich Escherichia-Shigella. Butyrate depletion elevates systemic lipopolysaccharide (LPS) levels and, via the gut-brain inflammatory route, activates mTORC1-integrated stress response (ISR) signaling in microglia. Consequently, microglia acquire a lipotoxic phenotype characterized by transcriptional up-regulation of DGAT- and ACSL-dependent lipid droplet (LD) biogenesis genes, accumulation of toxic lipids and inflammatory mediators, synaptic stripping, and memory loss. In vivo butyrate supplementation in PBAT-MP-exposed mice alleviates hippocampal pathology, normalizes microglial lipid accumulation, suppresses neuroinflammation, reduces ceramide levels, and improves cognitive performance. Mechanistically, butyrate inhibits mTORC1, attenuates eIF2α-ATF4-dependent ISR signaling, and represses DGAT/ACSL-dependent LD biogenesis, whereas microglial Rptor overexpression abolishes these protective effects, identifying mTORC1 as an upstream metabolic checkpoint. Collectively, our findings establish the microbiota-butyrate-mTORC1-ISR relay as a core driver of PBAT-MPs-induced neurotoxicity and highlight restoration of butyrate signaling as a promising microbiota-based strategy for preventing microplastic-induced brain lipotoxic injury.
    Keywords:  Butyrate; Gut–brain axis; Microglial lipotoxicity; PBAT microplastics; mTORC1–ISR signaling
    DOI:  https://doi.org/10.1186/s12974-026-03869-1
  6. Nat Commun. 2026 May 11.
    Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination.
    Seyyed Mohyeddin Ziaee, Shiva Nemati, Hardeep Kataria, Elisabet Jakova, Seyed Mojtaba Hosseini, Pejman Ghelich, Graham McLeod, Ali Tamayol, V Wee Yong, Soheila Karimi-Abdolrezaee.
      Impaired myelin repair, or remyelination, is a hallmark of progressive multiple sclerosis (MS) that drives brain degeneration and enduring neurological disabilities. Microglia crucially support remyelination through myelin phagocytosis and lipid metabolism. However, in chronic demyelinated MS lesions, microglia lose their reparative function by acquiring a foamy dysfunctional phenotype characterized by accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Here, we show a positive correlation between dysregulation of neuregulin-1 and impaired oligodendrocyte remyelination in mice with chronic demyelination. Therapeutic restoration of neuregulin-1 fosters myelin regeneration through microglia-dependent mechanisms. We demonstrate that Nrg-1 signaling supports microglia integrity and function in chronic demyelinated lesions by exploiting their capacity for the clearance of myelin debris and cholesterol recycling, biosynthesis and efflux. These findings signify the promise of neuregulin-1 as an endogenous target to facilitate microglia mediated-repair in progressive MS in which there is an unmet need for new treatments.
    DOI:  https://doi.org/10.1038/s41467-026-72639-7
  7. Neurobiol Dis. 2026 May 11. pii: S0969-9961(26)00192-0. [Epub ahead of print] 107447
    Immune receptor LAG3 regulates microglia function during Alzheimer's disease.
    Andrew T Perl, Juan Wu, John D Dong, Ashley M Brooks, Andrew R Yoblinski, Tia T Vierling, Jian-Liang Li, Dana R Ruby, Daniel Radzicki, Serena M Dudek, Jesse D Cushman, Elizabeta Gjoneska.
      Alzheimer's Disease (AD) remains the leading cause of dementia globally, yet the exact etiology is not well defined and effective treatments remain unavailable. Here, we report that deletion of the immune checkpoint receptor lymphocyte activation gene 3 (Lag3) in a familial AD mouse model, 5xFAD+, can rescue molecular, cellular and behavioral phenotypes of neurodegeneration. Specifically, we demonstrate that amyloidosis and microgliosis in the 5xFAD+ mice are significantly reduced by Lag3 deletion. Moreover, we show that Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes in the 5xFAD+ mice. Transcriptional profiling reveals that Lag3 deletion suppresses aberrant overexpression of disease associated microglia (DAM) genes in 5xFAD+ microglia, effectively restoring homeostatic transcriptional programs. Finally, we observe reduced CD8+ T cell infiltration in the brain of 5xFAD+ animals after Lag3 deletion which likely mediates molecular, cellular and behavioral effects resulting from microglia DAM gene activation. Our results highlight a previously unrecognized role for Lag3 in AD as a critical regulator of microglia function and suggest Lag3 might be a viable target for novel AD therapeutic interventions.
    Keywords:  Alzheimer's disease; Checkpoint, DAM; Lag3, immune; Microglia; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.nbd.2026.107447
  8. Neuron. 2026 May 14. pii: S0896-6273(26)00319-3. [Epub ahead of print]
    Cell-type-specific APOE4 cascade across the Alzheimer's disease continuum.
    David Shostak, Zherui Liang, Yadong Huang.
      Apolipoprotein E4 (APOE4) is the leading genetic risk factor and an increasingly recognized causal contributor to Alzheimer's disease (AD). AD progresses along a temporal, pathological, and clinical continuum spanning preclinical, prodromal, and dementia stages. Across this continuum, APOE4 exerts detrimental effects at distinct times and in different cell types, underscoring the need for a model defining not only how but also when and in which cells these effects occur. In this review, we synthesize current findings and propose a temporal model linking cell-type-specific APOE4 expression to AD progression. In this model, age-associated stress upregulates neuronal APOE4 expression, leading to early neuronal deficits characteristic of preclinical AD. Neuronal APOE4-induced damage subsequently triggers a harmful glial response that, alongside glial APOE4, amplifies neurodegeneration and accelerates the onset of prodromal and dementia AD. This model highlights the temporal and cellular dynamics of APOE4 effects and suggests stage- and cell-type-specific therapeutics targeting APOE4-driven mechanisms across the AD continuum.
    Keywords:  APOE-I3; APOE4; Alzheimer’s disease continuum; DAMP; SST interneuron; cascade; cell-type-specific; dementia; gliosis; hyperactivity; neurodegeneration; neuroinflammation; neuron; preclinical Alzheimer's disease; prodromal Alzheimer’s disease; tau; temporal
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.024
  9. Nature. 2026 May 13.
    Sustaining microglial reparative function enhances stroke recovery.
    Jun Tsuyama, Seiichiro Sakai, Kumiko Kurabayashi, Ayaka Nakamura, Eri Tanaka, Yuichiro Hara, Ito Kawakami, Makoto Tsuda, Takahiro Masuda, Marco Prinz, Hideya Kawaji, Takashi Shichita.
      Neurological symptoms after brain injury can remain as lifelong detrimental sequelae because most of the spontaneous recovery response disappears within a few months after the injury1,2. Microglia have an essential role in this process; however, the cellular and molecular mechanisms that diminish spontaneous functional recovery in the brain remain unclear. Here using cellular fate analysis, we show that reparative microglia persist in the brain after a stroke even after losing their beneficial functions. In these cells, ZFP384 is identified as a pivotal transcriptional regulator that diminishes the expression of genes associated with the recovery phase, turning them into dysfunctional microglia that lose their reparative functions. Mechanistically, ZFP384 diminishes the YY1-mediated chromatin interaction necessary to induce the expression of these genes in microglia. The use of antisense oligonucleotides that target Zfp384 can sustain the broad range of neural repair effects of microglia and enhance recovery after stroke, even in the chronic phase of ischaemic stroke. Thus, therapeutics that prevent the loss of reparative immunity-the beneficial restorative functions of immune cells-can prolong functional recovery in the brain.
    DOI:  https://doi.org/10.1038/s41586-026-10480-0
  10. J Neuroinflammation. 2026 May 13.
    SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
    Hui-Wen Zhang, Xue-Jie Wang, Mao-Mao Chu, Guang-Yuan Xing, Kai Qiu, Yu-Ge Zhang, Wen-Feng Zhang, Yu-Tong Zhang, Xue Liu, Lei Li, Xiao-Wei Lu, Xin-Xin Huang, Lei-Yang Zhang, Zhi-Yuan Zhang.
      Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in acute lipidomic profiling, reflecting global lipid alterations. Under physiological conditions, microglial lipid processing involves fatty acid uptake, storage, and mitochondrial oxidation. However, following TBI, excessive fatty acid uptake promotes lipid droplet accumulation, mitochondrial stress, and pro-inflammatory activation. In this study, we investigated whether modulating this process confers therapeutic benefits. Trilobatin (Tri), a natural flavonoid glycoside with potent immunometabolic modulatory activity, markedly reduced neuroinflammation and neuropathological damage while improving motor and cognitive performance in a mouse model of TBI. Integrated transcriptomic and metabolomic analyses revealed that Tri reduced excessive mitochondrial lipid accumulation, alleviated mitochondrial damage, and inhibited mitochondrial DNA release, thereby blocking the TLR9/MyD88/P-P65 pro-inflammatory pathway. Further screening and validation identified that Tri downregulates the lipid transporter SLC27A3, limits excessive lipid uptake, and consequently alleviates microglial pro-inflammatory responses driven by lipid overload. Collectively, these findings establish a link between microglial lipid metabolism and inflammatory activation and support trilobatin as a promising therapeutic agent targeting metabolic-inflammatory crosstalk in acute neural injury.
    Keywords:  Lipid reprogramming; Microglial immunometabolism; Mitochondrial lipotoxicity; Neuroprotection; SLC27A3; Trilobatin
    DOI:  https://doi.org/10.1186/s12974-026-03826-y
  11. Nat Commun. 2026 May 14.
    Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states.
    Xia Han, Gregory M Rosenberg, Vivianne M Kisling, Tao Zhang, Chia-Yi Lee, Ashvin Ravi, Mikhail Melnik, Tina Bilousova, Salvatore Spina, Alissa L Nana, Lea T Grinberg, William W Seeley, Karen H Gylys, Laura M Huckins, Towfique Raj, Kristen J Brennand, Jessica E Rexach.
      The accumulation of abnormal tau protein selectively affects distinct brain regions and specific populations of neurons and glial cells in tau-related dementias, such as Alzheimer's disease, Pick's disease and progressive supranuclear palsy. Although the three disorders share the feature of tau protein pathology, the regulatory circuitry of non-coding genetic variants underlying risk-associated cell states remains to be elucidated. Using paired single-nucleus profiling of chromatin accessibility and gene expression across the three conditions, we define cell-type-specific cis-regulatory elements across six cell types and fifty subclasses. Comparing disease-dynamic cis-regulatory elements across three disorders, we find that glia overrepresent disorder-specific gene regulation related to dynamic cellular response to stress. We show that human genetic variants affecting microglial gene regulation converge into distinct and co-regulated modules affecting specific cellular functions. Moreover, polygenic risk modifiers are maximally co-accessible in disorder-specific glial states, modifying distinct pathways such as sphingomyelin regulation in Pick's disease. Our study informs glial regulators linked to polygenic modifiers of primary tauopathy, establishing modifiable pathways governing resilience.
    DOI:  https://doi.org/10.1038/s41467-026-73007-1
  12. Acta Neuropathol Commun. 2026 May 14.
    Multimodal profiling of immune responses reveals innate-adaptive immune imbalance in human bornavirus encephalitis.
    Nicola Jungbäck, Przemyslaw Grochowski, Daniel Hieber, Moritz Dinser, Zuzanna Mielewczyk, Thomas Pfefferkorn, Birgit Muntau, Thomas Richter, Georg Rieder, Antonios Bayas, Klaus Hirschbühl, Bruno Märkl, Patrick Adam, Dennis Tappe, Friederike Liesche-Starnecker.
      Human bornavirus encephalitis (BVE) is a rare, emerging and fatal zoonotic disease mainly caused by the Borna disease virus 1 (BoDV-1), a non-cytolytic RNA virus. Despite increasing recognition, the immunopathogenesis of human BoDV-1 infection remains insufficiently characterised. Complete coronal and sagittal brain sections from four fatal BoDV-1 cases were analysed using digitised immunohistochemistry to quantify viral distribution and tissue responses. Transcriptome-based analyses characterised local immune cell profiles in relation to viral loads measured by RT-qPCR. BoDV-1 viral loads varied substantially between cases but showed region-specific enrichment in the basal ganglia and hippocampus, correlating with lymphocyte presence and reactive microglia and astrocytes. Immune cell deconvolution revealed viral load-dependent modulation dominated by innate immune and glial populations, including metabolic and reactive astrocyte states, IFNγ-responsive microglia, and dendritic cells, macrophages, neutrophils, basophils, and CD8⁺ T cells. This was accompanied by induction of interferon-stimulated genes, antigen presentation, protein synthesis, and oxidative stress pathways, with a transcriptional signature resembling non-lytic viral and autoimmune-like neuroinflammatory conditions rather than lytic infections. These findings support a model of BoDV-1 encephalitis characterised by a prominent innate immune response and comparatively limited adaptive immune signatures. This imbalance might potentially contribute to impaired viral clearance and extensive tissue damage, a possible relationship that warrants further investigation.
    Keywords:  BoDV-1; Encephalitis; Immunopathogenesis; Neurotropic virus; Transcriptome
    DOI:  https://doi.org/10.1186/s40478-026-02319-6
  13. Alzheimers Dement. 2026 May;22(5): e71463
    Single-cell transcriptomic analysis reveals APOE genotype-dependent sex differences in Alzheimer's disease.
    Gefei Yu, Abigail Thorpe, Qi Zeng, Erming Wang, Alison Goate, Dongming Cai, Minghui Wang, Bin Zhang.
       INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, with approximately two-thirds of AD patients being female. Basic and clinical research studies provide strong evidence that sex-specific differences contribute to AD complexity. Additionally, sex-specific interactions between apolipoprotein E (APOE) 𝜀4, the primary genetic risk factor of AD, and AD-associated neurodegenerative processes are well documented. However, there has been no comprehensive investigation into the interplay between sex and APOE genotypes at the single-cell level.
    METHODS: In this study, we systematically explore sex- and APOE-associated differences in single-cell transcriptomics in AD.
    RESULTS: Our work provides a high-resolution landscape of sex and APOE genotype-specific transcriptomic changes across 54 high-resolution cell types in AD and highlights genes and brain cell populations that show significant sex- and APOE-specific differences in AD.
    DISCUSSION: This study lays the groundwork for understanding the complex molecular mechanisms of AD and informs the development of targeted sex- and APOE-stratified interventions for AD.
    Keywords:  APOE; Alzheimer's disease; apolipoprotein E; sex difference; single cell; transcriptomics
    DOI:  https://doi.org/10.1002/alz.71463
  14. Int Immunopharmacol. 2026 May 09. pii: S1567-5769(26)00627-2. [Epub ahead of print]182 116781
    Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.
    Gong Chen, Cong Zhao, Chun Wang, Guochun Chen, Jingming Shi, Huihui Chen.
      Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Glaucoma; Immunity; Microglia; Multiple sclerosis; Neurodegenerative diseases; T cells
    DOI:  https://doi.org/10.1016/j.intimp.2026.116781
  15. Int J Mol Sci. 2026 Apr 22. pii: 3719. [Epub ahead of print]27(9):
    Microglial Plasticity in Vascular Dementia: Mechanisms and Therapeutic Reprogramming.
    Manish Shukla, Jarvis Li, Yan Sun, Rong Jin, Guohong Li.
      Vascular dementia (VaD) is a leading cause of cognitive decline and arises from heterogeneous cerebrovascular pathologies, most commonly cerebral small vessel disease and chronic cerebral hypoperfusion. Microglia, the brain's resident immune cells, exert a dual, stage-dependent influence during VaD progression, initially supporting neuroprotection through debris clearance and tissue repair, but later contributing to chronic neuroinflammation, synaptic loss, and white matter injury. Emerging evidence suggests that multiple molecular pathways, including purinergic receptors, Toll-like receptors and inflammasome cascades, complement-mediated synaptic pruning, and homeostatic and metabolic regulators, such as TREM2 (triggering receptor expressed on myeloid cells 2) and CSF1R (colony-stimulating factor 1 receptor), govern microglial functional transitions. Furthermore, post-transcriptional regulation by microRNAs (e.g., miR-30 family, miR-124, miR-146a, and miR-155) modulates these phenotypes, offering potential biomarkers and therapeutic targets. Understanding these interconnected molecular and epigenetic networks provides a framework for reprogramming microglia from pro-inflammatory to reparative states, thereby providing a mechanistic basis for precision interventions to preserve neurovascular integrity and mitigate cognitive impairment in VaD.
    Keywords:  microglia; microglial reprogramming; neuroinflammation; synaptic pruning; vascular dementia; white matter injury
    DOI:  https://doi.org/10.3390/ijms27093719
  16. J Neuroinflammation. 2026 May 11.
    IFI204 drives gasdermin D-mediated mitochondrial permeabilization to amplify neuronal pyroptosis in ischemic stroke.
    Pengfei Xu, Nan Shen, Tian Qiu, Mingyue Zhou, Rui Li, Chunrong Tao, Yuyou Zhu, Wei Hu.
      Gasdermin D (GSDMD)-mediated pore formation on mitochondrial membranes is known to exacerbate pyroptosis. The cytosolic DNA sensor interferon activated gene 204 (IFI204) can activate the inflammasome to induce pyroptosis. However, whether and how IFI204 regulates mitochondrial membrane permeabilization to drive pathological outcomes in ischemic stroke remains unclear. Here, using a mouse model of middle cerebral artery occlusion (MCAO), we demonstrate that IFI204 was predominantly expressed in neurons and increased to peak at 24 h after ischemic injury. Neuron-specific deletion of IFI204 alleviated cerebral infarction, reduced neuronal degeneration, and restored long-term sensorimotor coordination and cognitive function. These protective effects correlated with attenuated neuronal pyroptosis and mitochondrial dysfunction, as evidenced by decreased levels of GSDMD N-terminal fragment (GSDMD-N) and reduced mitochondrial colocalization. Conversely, adeno-associated virus-mediated re-expression of IFI204 in knockout mice restores these pathological features. In vitro, IFI204 is both necessary and sufficient to trigger this cascade. Transcriptomic profiling revealed a significant downregulation of the stimulator of interferon genes (STING) within the NOD-like receptor signaling pathway in IFI204-deficient neurons. Mechanistically, glutathione S-transferase (GST) pull-down assays confirmed a direct interaction between the pyrin domain (PYD) of IFI204 and STING. This interaction triggers caspase-1 activation and GSDMD cleavage, generating GSDMD-N, which subsequently forms pores specifically on mitochondrial membranes. These pyroptotic pores disrupted mitochondrial integrity, exacerbating dysfunction, and facilitating the cytosolic release of mitochondrial DNA (mtDNA), cytochrome c, and aconitase 2. Notably, the released mtDNA further activated IFI204, establishing a pathogenic feed-forward cycle that exacerbates mitochondrial damage and inflammatory neuronal death. Genetic ablation of STING partially abrogated the pyroptosis-promoting effect of IFI204. Collectively, these findings demonstrate that IFI204-driven cytosolic mtDNA sensing underlies a neuronal inflammatory mechanism responsible for pyroptosis and mitochondrial damage in ischemic stroke.
    Keywords:  GSDMD; IFI204; Ischemic stroke; Mitochondrial DNA (mtDNA); Neuroinflammation; Pyroptosis
    DOI:  https://doi.org/10.1186/s12974-026-03847-7
  17. J Neuroinflammation. 2026 May 13. pii: 156. [Epub ahead of print]23(1):
    A CSF disease-associated macrophage signature defines progressive multiple sclerosis.
    Anna-Lena Börsch, Frederike Riethues, Andreas Schulte-Mecklenbeck, Xuesong Wang, Michael Heming, I-Na Lu, Louisa Müller-Miny, Heinz Wiendl, Catharina C Gross, Raphaël Bernard-Valnet, Gerd Meyer Zu Hörste.
       OBJECTIVE: Progression in multiple sclerosis (MS) often corresponds to irreversible disability in MS patients. Cellular changes in the cerebrospinal fluid (CSF) have provided biomarkers and mechanisms in relapsing-remitting MS (RRMS) but remain understudied in primary and secondary progressive MS (summarized herein as PMS).
    METHODS: We combined retrospective flow cytometry of CSF cells from RRMS (n = 169), PMS (n = 56), and non-inflammatory controls (n = 74) with prospective CSF single-cell transcriptomics of 35 individuals (11 controls, 12 RRMS, and 12 PMS) and with confirmatory CSF ELISA. Available CSF single-cell data from age-matched and Alzheimer's disease (AD) patients served as additional controls.
    RESULTS: Proportions of CD14+ monocytes in CSF are increased in PMS and correlated with clinical surrogate markers of progression. Transcriptionally, these monocytes resembled border-associated macrophages (BAM)-like cells with a chronically activated antigen-presenting phenotype. Additionally, these monocytes shared some features with disease-associated microglia/macrophages (DAM), previously identified in neurodegeneration. Induction of DAM-associated molecules, including transcribed and soluble TREM2 (sTREM2), characterized secondary progressive MS (SPMS) and supported its differential diagnosis.
    INTERPRETATION: We thus identified MS stage-specific CSF signatures and shared cellular features of degeneration detectable in CSF of PMS patients.
    Keywords:  Cerebrospinal fluid; Progressive multiple sclerosis; Single-cell RNA-seq
    DOI:  https://doi.org/10.1186/s12974-026-03861-9
  18. Nat Aging. 2026 May 15.
    Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer's disease.
    Global Neurodegeneration Proteomics Consortium (GNPC)
      The APOE locus is the strongest genetic factor for Alzheimer's disease, with ε4 increasing and ε2 decreasing risk, yet the basis of these opposing effects remains unclear. Here we performed a multicohort proteomic analysis across plasma and cerebrospinal fluid in GNPC, BioFINDER-2, ADNI, UK BioBank, and PPMI. APOE-associated protein alterations are detectable before amyloid pathology and remain stable across age and disease progression. APOE2-associated proteins were enriched in pathways related to cellular maintenance and anti-inflammatory processes. By contrast, APOE4 showed a limited set of upstream mediators linked to cell-cycle and oligodendrocyte precursor cell biology, and a broader group of proteins reflecting vascular, immune, and proteostatic dysfunction shaped by downstream pathology. Comparative analyses highlighted allele-specific mediators and oppositely regulated proteins contributing to differential disease risk. Together, these findings reveal that APOE2 and APOE4 shape Alzheimer's disease risk through distinct molecular architectures and identify candidate biomarkers and targets for allele-specific interventions.
    DOI:  https://doi.org/10.1038/s43587-026-01123-0
  19. Cells. 2026 Apr 28. pii: 801. [Epub ahead of print]15(9):
    Early Müller Glial Activation and Retinal Ganglion Cell Synaptic Dysfunction in APP/PS1 Mice.
    Yuyan Zhou, Guibo Qi, Haoyang Zhou, Pifang Gong, Zhenru Wang, Xuan Song, Cheng Tian, Haixiang Wu, Song Qin.
      Alzheimer's disease (AD) is increasingly recognized as a multisystem neurodegenerative disorder in which sensory dysfunction accompanies cognitive decline. As an accessible extension of the central nervous system, the retina provides a valuable window for investigating early neurodegenerative processes; however, the cellular mechanisms underlying AD-associated retinal pathology remain incompletely understood. Here, using the APP/PS1 mouse model, we systematically examined structural, functional, and glial alterations in the retina across disease stages. Despite robust age-dependent amyloid plaque accumulation in visual-related brain regions, no plaque-like β-amyloid (Aβ) deposits were detected in the retina even at advanced ages. Nevertheless, young APP/PS1 mice exhibited early thinning of inner retinal layers, impaired retinal electrophysiological responses, and reduced excitatory synaptic inputs to retinal ganglion cells (RGCs), preceding overt neuronal loss. These neuronal changes were accompanied by pronounced Müller glial activation, characterized by upregulation of gliosis markers and extensive morphological remodeling. Functional analyses further revealed dynamic alterations in glial homeostasis, including early elevation followed by age-dependent decline of glutamine synthetase activity, together with increased expression and disrupted perivascular polarity of aquaporin-4. Consistently, transcriptomic profiling of young AD retinas identified coordinated dysregulation of genes involved in amino acid metabolism, transport, and oxidative stress responses. Together, our findings identify Müller glial remodeling as an early feature of AD-associated retinal pathology that coincides with synaptic vulnerability of RGCs and occurs independently of local Aβ plaque deposition, highlighting retinal glia as potential early indicators and modulators of neurodegeneration.
    Keywords:  Alzheimer’s disease; Müller glia; glial morphology; glutamine synthetase; retinal ganglion cells
    DOI:  https://doi.org/10.3390/cells15090801
  20. bioRxiv. 2026 Feb 23. pii: 2026.02.20.707075. [Epub ahead of print]
    Phagocytosis deficient glia display phagosome processing defects and macrophage recruitment to the brain of adult Drosophila melanogaster.
    Guangmei Liu, Iqra Amin, Cheng Yang Shi, Kimberly McCall.
      Efficient clearance of dying cells is essential for brain homeostasis, yet how partial defects in phagocytic processing affect neuroimmune interactions during aging remains unclear. In the adult Drosophila brain, glia function as professional phagocytes through the conserved engulfment receptor Draper (Drpr). Here, we show that glial loss of Drpr does not completely eliminate phagocytosis but instead leads to persistent, age-dependent inefficiency in corpse degradation. Using a genetically encoded pH-sensitive reporter to visualize acidified phagocytic compartments, we find that drpr -deficient glia retain residual engulfment activity but progressively accumulate enlarged, incompletely degraded phagocytic cargo. This chronic clearance defect coincides with altered immune dynamics at the central nervous system periphery, including increased recruitment and adhesion of peripheral hemocytes at the blood-brain barrier (BBB), without overt BBB disruption. Notably, hemocytes at the brain surface can phagocytose glial material in a Drpr-dependent manner, revealing a form of barrier-associated "border clearance". Together, these findings demonstrate that inefficient corpse degradation is sufficient to reshape neuroimmune interactions during aging.
    Main points: Draper-deficient glia still engulf corpses but fail phagolysososomal degradation.Impaired glial clearance reshapes immune dynamics at the CNS periphery.With intact BBB, hemocytes that accumulate on the aging brain surface engulf glial debris.
    DOI:  https://doi.org/10.64898/2026.02.20.707075
  21. Int J Mol Med. 2026 Jul;pii: 178. [Epub ahead of print]58(1):
    miR‑223‑3p promotes microglial lactylation and M1 polarization via the FBXW7/Notch1/Hes1/SIRT1 axis.
    Xiaoyu Wang, Lin Song, Jiafeng Wang, Qianqian Xie, Yan Wang, Chunyan Li, Tianqi Wang, Yifeng Du.
      Neuroinflammation is a hallmark of Alzheimer's disease (AD) and is closely linked to microglial M1 polarization. In the present study, miR‑223‑3p was identified as a critical regulator of microglial metabolic reprogramming. Analyses of Gene Expression Omnibus and AD Neuroimaging Initiative datasets revealed significant upregulation of miR‑223‑3p in the brain, blood, and cerebrospinal fluid of patients with AD. The overexpression of miR‑223‑3p promoted M1 polarization and increased reactive oxygen species (ROS) levels. Transcriptomic, metabolomic and Seahorse analyses revealed increased glycolysis, lactate production and lactylation, whereas inhibition of lactylation reduced M1 polarization and ROS accumulation. Mechanistically, miR‑223‑3p suppressed SIRT1 expression and directly targeted FBXW7, leading to activation of the Notch1/Hes1 pathway and further suppression of SIRT1. In summary, these findings demonstrate that miR‑223‑3p drives microglial lactylation‑mediated M1 polarization through the FBXW7/Notch1/Hes1/SIRT1 signaling axis. The present study provides new insight into the role of lactylation in neuroinflammation and highlights miR‑223‑3p as a potential therapeutic target for AD.
    Keywords:  Alzheimer's disease; SIRT1; lactylation; microRNA‑223‑3p; microglial M1 polarization
    DOI:  https://doi.org/10.3892/ijmm.2026.5849
  22. Nat Commun. 2026 May 09.
    Inter-organ metabolic feedback via BCAA catabolism regulates glucagon-like hormone secretion in Drosophila.
    Takashi Nishimura, Chisei Arakawa, Yuto Yoshinari.
      Metabolic homeostasis regulated by nutrient-responsive endocrine hormones is essential for organismal survival. In insects, lipid and carbohydrate mobilization is controlled by adipokinetic hormone (Akh), a glucagon-like peptide secreted from neuroendocrine cells. However, whether Akh secretion is subject to negative feedback via its downstream catabolic effects remains unclear. Here, we develop a quantitative assay for Akh using tandem mass spectrometry and show that inter-organ metabolic communication regulates Akh secretion during starvation in Drosophila. Metabolic profiling reveals that Akh signaling in the fat body promotes branched-chain amino acid (BCAA) catabolism by inducing BCAA transaminase (Bcat). Loss of Akh signaling impairs clearance of BCAAs derived from fat body autophagy, resulting in Akh hypersecretion. BCAA catabolism is coupled to glutathione biosynthesis and redox homeostasis during nutrient stress. Our findings reveal a feedback mechanism in which Akh signaling regulates its own secretion via amino acid catabolism, linking energy mobilization to redox homeostasis during starvation.
    DOI:  https://doi.org/10.1038/s41467-026-72677-1
  23. Nat Aging. 2026 May 12.
    Somatic variants in microglia-like cells linked to Alzheimer's disease pathology.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-026-01135-w
  24. Sci Rep. 2026 05 09. pii: 14687. [Epub ahead of print]16(1):
    Microglia-specificity of different markers is overridden in glioblastoma specimens.
    Alexander D Bungert, Aminaa Sanchin, Anne Blank, Monika Jüngst-Mieczkowska, Annett Müller, Matthäus Felsenstein, Kati Turkowski, Wenying Zhang, Peter Vajkoczy, Susan Brandenburg.
      Microglia are the resident immune cells of the central nervous system. When glioblastoma develops, microglia and peripheral macrophages accumulate within the tumor tissue. Since both cell populations presumably exhibit different functional properties with anti- and pro-tumor characteristics, it is essential to distinguish between these cell populations accurately. The widespread and extensive use of single-cell technologies allowed the discovery of novel microglial markers like Sall1, Tmem119, P2ry12 and Hexb that were used for discrimination of populations. In our study, these markers were tested on protein level using immunofluorescence staining. This method permits easy identification by co-staining with IBA1 as lineage marker for myeloid cells. Bone marrow chimeras served as differentiation control. Staining showed ubiquitous marker expression of microglia in both murine naïve brains and human epilepsy specimens. However, experiments using a murine glioblastoma model demonstrated that macrophages can also express these markers after infiltrating the brain and tumor tissue. Furthermore, the level of expression varies spatially, decreasing towards the intratumoral area. In vitro experiments confirmed positive staining results for both microglia and macrophages. Furthermore, cultivation with tumor-conditioned medium led to downregulation of microglial markers. Consequently, the concept that SALL1, TMEM119, P2RY12, and HEXB are exclusive markers for microglia depends strongly on the experimental and pathological conditions, and should not be generalized. Under neuroinflammatory conditions, cell specificity of the examined markers largely diminishes and both microglia and macrophages show ubiquitous expression. Considering this fact should lead to a context dependent application when using these markers to identify myeloid cell populations within the brain.
    Keywords:  Glioblastoma; Macrophages; Microglia; P2RY12; SALL1; TMEM119
    DOI:  https://doi.org/10.1038/s41598-026-52315-y
  25. Immunity. 2026 May 12. pii: S1074-7613(26)00168-8. [Epub ahead of print]59(5): 1171-1173
    CD8+ T cells turn resilient under stress.
    Daniele C Nascimento, Luciana Berod.
      Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving effector function and supporting antitumor immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.006
  26. J Clin Invest. 2026 May 15. pii: e190954. [Epub ahead of print]136(10):
    Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons.
    Tae Wan Kim, Jinghua Piao, Vittoria D Bocchi, So Yeon Koo, Se Joon Choi, Fayzan Chaudhry, Donghe Yang, Hyein S Cho, Emiliano Hergenreder, Lucia Ruiz Perera, Subhashini Joshi, Zaki Abou Mrad, Nidia Claros, Shkurte Ademi Donohue, Yeong Eun Im, Hyo Jae Jeong, Anika K Frank, Ryan M Walsh, Eugene V Mosharov, Doron Betel, Viviane Tabar, Lorenz Studer.
      While clinical trials of human pluripotent stem cell-derived midbrain dopamine (mDA) neuron precursor grafts for Parkinson's disease (PD) are ongoing, current protocols remain suboptimal. In particular, the yield of TH+ mDA neurons after in vivo grafting and the expression of certain mDA neuron and subtype-specific markers require improvement. Single-cell transcriptomic analyses of grafts have revealed low proportions of mDA neurons and substantial off-target contamination. Here, we present an optimized mDA neuron differentiation strategy that builds on our clinical-grade ("Boost") protocol by adding FGF18 and IWP2 treatment ("Boost+") at the neurogenesis stage. Boost+ mDA neurons show higher expression of EN1, PITX3, and ALDH1A1. Improvements in mDA neuron yield and transcriptional similarity to primary mDA neurons are observed in vitro and following transplantation. Single-nucleus RNA sequencing demonstrates enrichment of A9 mDA neurons within Boost+ grafts. Functional studies in vitro demonstrate increased dopamine production and release and improved electrophysiological properties. In vivo analyses show higher percentages of TH+ mDA neurons, resulting in efficient rescue of amphetamine-induced rotation behavior in the 6-OHDA rat model and rescue of deficits in some nondrug-induced assays, including the ladder rung assay, which are not improved by Boost mDA neurons. The Boost+ conditions present an optimized differentiation protocol with advantages for disease modeling and mDA neuron grafting paradigms.
    Keywords:  Development; Neurodevelopment; Neuroscience; Parkinson disease; Stem cell transplantation
    DOI:  https://doi.org/10.1172/JCI190954
  27. J Immunol. 2026 Apr 15. pii: vkag076. [Epub ahead of print]215(4):
    Serpine1 regulates Th17 cell differentiation and exacerbates IMQ-induced skin inflammation.
    Kaidireya Saimaier, Ling Xie, Chun Wang, Jie Lv, Guangyu Liu, Sanxing Han, Chunliang Li, Changsheng Du.
      A large body of evidence indicates that Th17 cells play essential roles in mucosal immune responses and trigger autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, and psoriasis. Targeting Th17 cells holds promise for therapeutic innovation. While the core cytokine signaling networks driving Th17 differentiation have been extensively characterized, the roles of non-canonical secreted factors in Th17 polarization and pathogenicity remain incompletely understood. Here, we found that Serpine1 was preferentially induced in Th17 cells. Genetic ablation of Serpine1 inhibited Th17 cell polarization in vitro, reproducing the phenotype observed with pharmaceutical inhibition of PAI-1, the product of Serpine1. Furthermore, in a TLR7/8-driven inflammatory skin model induced by imiquimod (IMQ), deletion or inhibition of Serpine1 significantly attenuated disease severity and reduced skin inflammation. Notably, this protective effect was also recapitulated in T cell-specific Serpine1 conditional knockout mice, confirming a T cell-intrinsic role for Serpine1 and ruling out non-T-cell-autonomous effects. Collectively, our results revealed a critical and T cell-intrinsic role for Serpine1 in Th17 differentiation and autoimmune pathology, suggesting that Serpine1/PAI-1 may contribute to Th17-mediated inflammation.
    Keywords:  PAI-1; Th17; autoimmune disease; psoriasis; serpine1
    DOI:  https://doi.org/10.1093/jimmun/vkag076
  28. Cells. 2026 May 04. pii: 840. [Epub ahead of print]15(9):
    Microglia Reprogramming in Glioblastoma: Stem Cell-Derived Factors as Emerging Immunomodulators.
    Zahra Amiri, Beatrice Federica Tremonti, Alessandro Corsaro, Alessandra Pattarozzi, Adriana Bajetto, Federica Barbieri, Stefano Thellung, Tullio Florio.
      Glioblastoma (GBM) remains one of the most challenging forms of cancer to treat, despite that extensive molecular profiling is now available. Indeed, intratumoral cellular heterogeneity, receptor redundancy, and adaptive resistance through compensatory signaling limit the impact of targeted therapies. Moreover, immunotherapies also underperform: checkpoint blockade and vaccine strategies did not obtain consistent benefits in a low mutational burden, poorly immunogenic tumor microenvironment (TME) dominated by immunosuppressive myeloid cells. In this article, we provide evidence that tumor-associated macrophages (TAMs), a form of CNS resident microglia and infiltrating macrophage, derived from bone marrow, adopt a spatially and transcriptionally distinct, non-binary continuum, shaped by tumor-derived signals and niche constraints, allowing glioma cells to resist to immune and pharmaceutical therapeutics. Metabolic rewiring, including hypoxia-linked glycolytic pressure, lactate signaling, and lipid-associated programs, determine immunosuppressive outputs and restrict plasticity, while epigenetic imprinting (DNA methylation, histone modifications, and chromatin regulators) stabilizes these programs and limits access to inflammatory loci. We discuss how stem cell secretome, and extracellular vesicles (EVs) and their cargo may act as tunable autocrine/paracrine inputs that may bias microglial regulatory control. Finally, we highlight major translational confounders, including EV operational definitions, blood-brain barrier (BBB) permeability and regional exposure, inconsistent dosing units, mixed myeloid compartments, and manufacturing dependent variability. Therefore, an exposure-aware framework that integrates product identity, delivery evidence, state-sensitive potency assays, and functional endpoints would be highly desirable.
    Keywords:  epigenetic reprogramming; extracellular vesicles; glioblastoma; immunosuppression; metabolic reprogramming; microglia reprogramming; potency assays; stem cell secretome; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cells15090840
  29. Mol Neurobiol. 2026 May 15. pii: 633. [Epub ahead of print]63(1):
    Amyloid Plaques Ameliorate Memory Deficits and Hippocampal Neuron Loss in an Aβ4-42-Driven Alzheimer's Disease Mouse Model.
    Silvia Zampar, Merle Fricke, Florian Kremser, Ivan Talucci, Hans Michael Maric, Hans-Wolfgang Klafki, Agueda Rostagno, Olaf Jahn, Sascha Weggen, Jorge Ghiso, Oliver Wirths.
      Extracellular deposition of amyloid-β (Aβ) peptides in the form of plaques is the most prominent pathological hallmark of Alzheimer's disease (AD). The postulated central pathophysiological role of fibrillary Aβ plaques has, however, been questioned, and small, soluble, pre-fibrillar Aβ aggregates (oligomers) have been implicated as the crucial neurotoxic species in AD etiology. While the relationship between insoluble amyloid plaques and soluble Aβ oligomers remains unclear, it has been hypothesized that plaques may serve as reservoirs, sequestering toxic Aβ oligomers in the initial stages of the disease. Next to the canonical "full-length" Aβ1-40 and Aβ1-42 peptides, a variety of N-terminally truncated Aβ variants are present in AD brain tissue, with Aβ4-42 peptides showing high abundance. The detrimental effects of these N-terminally truncated peptides have been previously studied using the Tg4-42hom mouse line, which displays neuron loss and cognitive deficits and accumulates Aβ4-42 peptides in the CA1 region of the hippocampus albeit without amyloid plaque formation. This study aimed to investigate the relationship between soluble Aβ4-42 peptides and insoluble extracellular Aβ deposits by crossing the Tg4-42hom line with the plaque-bearing 5XFAD mouse model. We found that extracellular amyloid deposits in the hippocampus did not aggravate spatial memory deficits in Tg4-42hom mice but rescued recognition memory deficits. Moreover, while proximal CA1 pyramidal neuron loss in the hippocampus of Tg4-42hom mice was not affected by crossing with the 5XFAD line, a reduced loss of distal pyramidal neurons was observed in the filial line. Biochemically, 5XFAD/Tg4-42hom mice showed a trend towards increased levels of insoluble Aβ4-x peptides in the hippocampus. Taken together, these findings support the importance of soluble Aβ oligomers in the pathogenesis of AD and provide evidence for the hypothesis that amyloid plaques provide buffering capacity.
    Keywords:  Abeta; Alzheimer’s disease; Amyloid pathology; Behavior; Mouse model; N-terminal truncation; Neuron loss
    DOI:  https://doi.org/10.1007/s12035-026-05912-x
  30. Nature. 2026 May 13.
    Growth charts reveal how the brain's 'communication highways' change throughout life.
      
    Keywords:  Brain; Developmental biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-01318-w
  31. bioRxiv. 2026 Feb 26. pii: 2026.02.25.707973. [Epub ahead of print]
    Sphingolipid regulation by yeast Mdm1 supports adaptive remodeling of the methionine transporter Mup1.
    Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Scott Miller, Anne Ostermeyer-Fay, Daniel Canals, Xun Bao, Jing Li, Hanaa Hariri.
      Membrane lipid composition influences endocytic remodeling of nutrient transporters, yet how lipid metabolism is spatially coordinated to support sustained adaptation to nutrient limitations remains unclear. Here, we investigated whether the ER-vacuole tether Mdm1 links sphingolipid homeostasis to regulation of the high-affinity methionine permease Mup1 in budding yeast. To test this, we examined Mup1 trafficking, amino acid homeostasis, and sphingolipid composition in mdm1 Δ cells during starvation. We found that loss of Mdm1 causes persistent retention of Mup1 at the plasma membrane, accompanied by reduced intracellular methionine and broad amino acid depletion. Lipidomic analyses revealed decreased sphingoid bases and altered ceramide composition in mdm1 Δ cells. Importantly, supplementation with the sphingolipid precursor phytosphingosine restored sphingolipid pools, rescued Mup1 endocytosis, and improved amino acid homeostasis. Consistent with a chronic amino acid restriction-like state, mdm1 Δ cells exhibited extended chronological lifespan. Together, these findings identify Mdm1 as a spatial organizer of sphingolipid metabolism required for adaptive endocytic remodeling of Mup1, thereby linking ER-vacuole contact site function to plasma membrane proteostasis and metabolic adaptation.
    DOI:  https://doi.org/10.64898/2026.02.25.707973
  32. Nat Commun. 2026 May 13.
    ABL kinases regulate FGF signaling independent of CRK phosphorylation to prevent Peters anomaly type II.
    Hao Wu, Yingyu Mao, Qian Wang, Honglian Yu, Michael Bouaziz, Neoklis Makrides, Enpeng Wang, Zhipeng Ding, Anthony J Koleske, Glenn L Radice, Jerry Hsu, Xin Zhang.
      Peters anomaly is an anterior segment dysgenesis and a leading cause of congenital corneal opacity. Here, we show that loss of ABL kinases restores lens induction in the absence of FGF signaling but induces Peters anomaly type II independently of ERK signaling, a phenotype also observed with elevated FGF-Ras activity. This defect is rescued by allelic deletion of the ABL substrates CRK and CRKL. Contrary to prevailing models, ABL kinases do not act through direct phosphorylation of CRK proteins; instead, they phosphorylate PTPN12, suppressing p130CAS phosphorylation and CRK recruitment required for RHO GTPase activation. ABL kinase deficiency reduces actomyosin contractility in the lens vesicle and genetically interacts with RHOA inhibition, whereas RAC1 inhibition ameliorates disease phenotypes. These findings define an ABL-PTPN12-p130CAS pathway that controls cytoskeletal tension during lens vesicle separation and suggest that modulation of this process may offer a therapeutic approach for Peters anomaly type II.
    DOI:  https://doi.org/10.1038/s41467-026-72489-3
  33. bioRxiv. 2026 Feb 26. pii: 2025.04.23.650151. [Epub ahead of print]
    Deployment of endocytic machinery to periactive zones of nerve terminals is independent of active zone assembly and evoked release.
    Javier Emperador-Melero, Steven J Del Signore, Kevin M De León González, Pascal S Kaeser, Avital Adah Rodal.
      In presynaptic nerve terminals, the endocytic apparatus rapidly restores synaptic vesicles after neurotransmitter release. Many endocytic proteins localize to the periactive zone, a loosely defined area adjacent to active zones. A prevailing model posits that recruitment of these endocytic proteins to the periactive zone is activity-dependent. We here show that periactive zone targeting of endocytic proteins is largely independent of active zone machinery and synaptic activity. At mouse hippocampal synapses and Drosophila neuromuscular junctions, pharmacological or genetic silencing resulted in unchanged or increased levels of endocytic proteins including Dynamin, Amphiphysin, Nervous Wreck, Endophilin A, Dap160/Intersectin, PIPK1γ and AP-180. Similarly, disruption of active zone assembly via genetic ablation of active zone scaffolds at each synapse did not impair the localization of endocytic proteins. Overall, our work indicates that endocytic proteins are constitutively deployed to the periactive zone and supports the existence of independent assembly pathways for active zones and periactive zones.
    DOI:  https://doi.org/10.1101/2025.04.23.650151
  34. Eur J Pharmacol. 2026 May 13. pii: S0014-2999(26)00454-1. [Epub ahead of print] 178972
    Neuroinflammatory diseases triggered by cerebral hemorrhage: microglial iron accumulation and ferroptosis.
    Xue Gao, Hongxia Li, Jiqiang Liang, Shunfeng Liu.
      After a cerebral hemorrhage (CH), heme oxygenase-1 (HO-1) catalyzes the conversion of heme to release Fe2+. Microglia are the primary cells responsible for immune function in the brain. Upon the uptake of heme and iron ions, microglia are activated, leading to the subsequent release of inflammatory mediators and reactive oxygen species. Neuroinflammation and oxidative stress are common features of various brain diseases. Cerebral hemorrhage can trigger microglial iron accumulation and ferroptosis, which in turn leads to neuroinflammation and oxidative stress imbalance in the brain. Therefore, inhibiting microglial iron accumulation and ferroptosis alleviates cerebral hemorrhage-mediated neural damage and counteracts various brain diseases induced by it. We propose that the occurrence of many brain diseases is influenced by the location of cerebral microbleeds, suggesting that cerebral microbleeds may be a high-risk factor for inducing these diseases.
    Keywords:  Cerebral hemorrhage; cerebral microbleeds; ferroptosis; iron accumulation; microglia; neuroinflammation
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178972
  35. Front Immunol. 2026 ;17 1783755
    Microglia in autism spectrum disorder: heterogeneity, immunometabolism, and synapse-related pathways.
    Aojie Lian, Mei He, Hong Zhang, Yingmei Yang.
      Microglia are increasingly implicated in autism spectrum disorder (ASD), but their role remains difficult to define because the available evidence is heterogeneous in cohort composition, developmental stage, sampled brain region, and experimental modality. This Review summarizes current evidence on three related aspects of ASD-relevant microglial biology: microglial heterogeneity, immunometabolic regulation, and synapse-related pathways. Human postmortem studies, bulk transcriptomics, single-cell and spatial atlases, methylomic deconvolution, and in vivo neuroimmune imaging collectively support the presence of immune- and glia-associated alterations in at least a subset of ASD brains, but these findings do not support a single ASD-wide microglial phenotype. Instead, current evidence is more consistent with region-, stage-, sex-, and context-dependent microglial variation that should be interpreted together with neuronal, astrocytic, vascular, and broader tissue-level changes. We further review how lipid handling, mitochondrial function, phagocytic-lysosomal load, and bioactive lipid signaling may influence microglial competence in ASD-relevant settings, while noting that much of the detailed mechanistic immunometabolism literature still derives from aging and neurodegeneration. At the microglia-synapse interface, complement deposition, phosphatidylserine exposure, anti-engulfment checkpoints, and astrocyte-microglia crosstalk provide more informative mechanistic entry points than broad activation terminology. Across studies, the major challenge is not whether microglia are involved in ASD, but how to distinguish primary pathogenic effects from secondary adaptation, and how to relate molecular signatures to excessive, insufficient, or mistargeted synaptic remodeling. Overall, the literature supports a more precise interpretation of ASD-related microglial biology based on developmental timing, cellular context, and mechanism-linked readouts rather than non-specific inflammatory labels alone.
    Keywords:  TSPO PET; astrocyte-microglia crosstalk; autism spectrum disorder; complement; developmental timing; immunometabolism; microglia; synaptic pruning
    DOI:  https://doi.org/10.3389/fimmu.2026.1783755
  36. Int J Mol Sci. 2026 Apr 29. pii: 3984. [Epub ahead of print]27(9):
    Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.
    Qingru Wu, Jing Tian, Yan Gu, Xiaoying Bi, Hailing Zhang.
      Depression is a highly heterogeneous psychiatric disorder with its pathogenesis increasingly linked to dysregulated neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), play a pivotal role in the initiation and progression of the neuroinflammation and the pathophysiology of depression. These cells exhibit a dual role in pro- and anti-inflammatory processes, dynamically regulating immune responses through immunometabolic reprogramming in response to environmental cues. This review elaborates how metabolic remodeling in microglia, particularly within glucose, lipid, and amino acid pathways, drives their polarization toward a pro-inflammatory phenotype. This shift promotes depression pathogenesis via the release of inflammatory factors, disruption of synaptic plasticity, and mediation of neurotoxicity. We further discuss the impact of existing antidepressants on cellular metabolism and highlight the promise and challenges of targeting specific microglial metabolic pathways as a novel therapeutic strategy. This synthesis provides new insights into the immunometabolic mechanisms of depression and outlines directions for developing targeted treatments.
    Keywords:  depression; glutamate; glycolysis; immunometabolism; lipid metabolism; metabolic reprogramming; microglia; mitochondria; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms27093984
  37. Nat Neurosci. 2026 May 12.
    Optics-free spatial genomics for mapping mammalian brain aging by IRISeq.
    Abdulraouf Abdulraouf, Weirong Jiang, Zehao Zhang, Zihan Xu, Ziyu Lu, Tiffany Merlinsky, Andrew Liao, Ahmet Doymaz, Samuel Isakov, Tanvir Raihan, Wei Zhou, Junyue Cao.
      Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed sequencing to profile tissues at adjustable sizes and resolutions (5-50 µm). We applied IRISeq to map gene expression across more than 70 coronal sections from both adult and aged mouse brains, including wild-type and two lymphocyte-deficient models (Rag1 and Prkdc mutants) and generated more than 460,000 spatial transcriptome profiles. Our integrated analysis with 783,264 single-cell transcriptomes revealed region-specific aging signatures that are lymphocyte dependent, notably a downregulation of interferon signaling and inflammation in ventricular regions upon lymphocyte depletion, alongside mutant-specific upregulation of senescence pathways. Furthermore, lymphocyte deficiency was linked to preserved abundance of ependymal cells that line the brain's ventricles and to distinct microglial state dynamics, highlighting a key role for lymphocytes in driving inflammatory processes during brain aging. Overall, IRISeq provides a high-throughput and cost-effective solution for spatially resolved transcriptomic profiling, opening new avenues for elucidating region-specific cellular mechanisms underlying aging and identifying potential therapeutic targets to preserve brain homeostasis.
    DOI:  https://doi.org/10.1038/s41593-026-02293-1
  38. Neuron. 2026 May 11. pii: S0896-6273(26)00315-6. [Epub ahead of print]
    Intrinsic endothelial remodeling drives brain capillary repair.
    Jacqueline Condrau, Chaim Glück, Matthias T Wyss, Ladina Hösli, Eva Erlebach, Henri S Zanker, Alexandra von Faber-Castell, Luca Ravotto, Gina Eberle, Srinivasa R Allu, Tatiana V Esipova, Thomas Troxler, Jeffrey L Bennett, Marina Herwerth, Susanne Wegener, Aiman S Saab, Sergei A Vinogradov, Mohamad El Amki, Bruno Weber.
      The brain's microvasculature is essential for oxygen and nutrient delivery; however, the mechanisms underlying cerebral capillary repair following injury remain largely elusive. Here, we identify an unrecognized mechanism through which brain capillary endothelial cells (ECs) autonomously promote capillary remodeling. Using longitudinal two-photon imaging in mice, we demonstrate that following focal endothelial injury and selective loss of a single EC, neighboring ECs extend their plasma membranes toward each other, rapidly re-establishing capillary continuity and blood flow within 24-48 h. This repair process engages vascular endothelial growth factor receptor 2 (VEGFR2) signaling but occurs independently of perivascular or glial cell involvement. Finally, we reveal regional differences in repair efficacy, with hippocampal capillaries exhibiting a slower and less-efficient response compared with those in the cortex. These findings reveal an intrinsic mechanism that safeguards microvascular integrity and suggest that regional vulnerabilities in endothelial repair could shape brain resilience to injury and disease.
    Keywords:  brain endothelium; capillary repair; cerebral microvasculature; endothelial cell death; endothelial remodeling; in vivo two-photon imaging; microstroke; microvascular dynamics; stroke
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.020
  39. Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2525028123
    PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer's disease model.
    Aanishaa Jhaldiyal, Manisha Kumari, Lauren C Guttman, Trupti Tripathi, Mohammed Repon Khan, Justin Wang, Devanik Biswas, Abhishek Pasupuleti, Akansha Aggarwal, Shraddha Pandya, Shih-Ching Chou, Nikhil Panicker, Abhay Monghekar, Marilyn Albert, Lynn M Bekris, James B Leverenz, Tae-In Kam, Ted M Dawson, Valina L Dawson.
      Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-beta (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive enzyme-linked immunosorbent assay, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric Aβ1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein and BACE1 levels, altered γ-secretase complex composition, and enhanced Aβ degradation via neprilysin. These findings position PARP1 as a critical mediator of Aβ toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD.
    Keywords:  Alzheimer’s disease; PARP; amyloid beta (Aβ); neurodegeneration; poly(ADP-ribose) (PAR)
    DOI:  https://doi.org/10.1073/pnas.2525028123
  40. J Alzheimers Dis. 2026 May 11. 13872877261449395
    Non-economic social deprivation and cognitive functioning later in life: Results from the DELCODE study.
    DELCODE study group
      BackgroundLow socioeconomic status is associated with a higher risk for a number of health conditions, including cognitive impairment.ObjectiveWhile the association with economic indicators has been well researched, aim of this paper was to investigate specifically the association between non-economic social deprivation and cognitive functioning later in life.MethodsParticipants without objective cognitive impairment at baseline (n = 91 controls, n = 106 with subjective cognitive decline) of the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) filled out a posthoc survey on social deprivation. Factor analysis identified four non-economic domains of social deprivation (Residential area conditions, Accessibility, Neighborhood support, Household distress). Cognition was assessed via the CERAD neuropsychological battery. Analyses were conducted using linear regression models as well as maximum-likelihood mixed-effects models adjusted for age, gender, years of education, marital status, depression, BMI, heart disease, hypercholesterolemia, hypertension, and diabetes.ResultsAt the time of the survey, cognitive functioning was significantly lower among participants with high deprivation (b = -0.21, p = 0.037). These participants also had a faster rate of cognitive decline (b = -0.07, p = 0.006). Analyses of the deprivation sub-scores revealed statistically significant effects only for Accessibility (b = -0.31, p = 0.001; rate of cognitive decline b = -0.07, p = 0.004).ConclusionsOur findings suggest that non-economic social deprivation, especially in terms of access to a grocery store, pharmacy, postal office, and bus stop, might be relevant for maintaining cognitive functioning in old age. Further research should explore potential mechanisms of how these environmental conditions affect brain aging and neurodegenerative processes.
    Keywords:  Alzheimer's disease; cognitive decline; disparities; mild cognitive impairment; social deprivation; socioeconomic; subjective cognitive impairment
    DOI:  https://doi.org/10.1177/13872877261449395
  41. Acta Neuropathol Commun. 2026 May 14.
    Investigation of the myelin-amyloid interplay in Alzheimer's disease: insights from novel dsCMA imaging in mouse and human brains.
    Hanpeng Xu, Sumit Nanda, Jiandong Sun, Mitchell Rudd, Lin Gou, Haley Marks, Christopher K Williams, Shino Magaki, Harry V Vinters, Houri Hintiryan, Hong-Wei Dong.
      Myelin deterioration impairs neural communication and may contribute to neurodegenerative diseases such as Alzheimer's disease (AD). However, the spatiotemporal relationship between myelin degeneration and AD pathology remains unclear. We developed a novel imaging method-double-scan Cyto- and myelo-architecture (dsCMA)-that integrates multi-fluorescent labeling of cytoarchitecture and pathological markers with brightfield myelin staining on the same tissue sections. Coupled with computational tools for automated detection and quantification of amyloid-beta (Aβ) plaques and myelinated axons, dsCMA enables systematic analysis of Aβ-myelin interactions in 5xFAD mice and postmortem human AD tissues. In mice, we identified progressive, region-specific myelin disruption associated with Aβ accumulation, particularly in the hippocampus and cortex. Human samples revealed variable Aβ-myelin spatial relationships across individuals and regions, with evidence supporting a potential myelin origin for some plaques. These findings offer new insights into Aβ-myelin interplay and establish dsCMA as a scalable platform for histopathological analysis in translational and longitudinal AD research.
    DOI:  https://doi.org/10.1186/s40478-026-02317-8
  42. Alzheimers Res Ther. 2026 May 14.
    Cellular state heterogeneity underlying sex differences in Alzheimer's disease based on single-cell transcriptome.
    Zhiyi Wu, Qinglong Tan, Fei Xue, Zhuotong Jiang, Hongyu Zhao, Yuting Zhang, Yiming Liu, Yu Zhang, Danli Ding, Hongping Chen, Yingqi Xu, Feng Li, Chunlong Zhang.
       BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. However, the molecular mechanisms underlying sex differences in AD remain poorly understood.
    METHODS: In this study, we curated 3,302,741 single-nucleus or single-cell profiles from 603 samples (296 female and 307 male samples; 339 AD and 264 normal) across 10 cohorts to investigate sex-specific differences in the brain of individuals with and without AD. Focusing on six major cell types, we applied non-negative matrix factorization at the sample level to identify cell type -specific meta-programs (MPs). These MPs consist of mutually exclusive and functionally orthogonal gene set, representing different functional states of brain cells. Using these MPs, we characterized cellular states (CSs) across four sex-disease groups. We then examined sex differences in both AD and normal brains at the level of cellular states, with emphasis on metabolism, cell-cell communication, senescence, and disease relevance.
    RESULTS: Metabolic profiling revealed that inflammatory homeostasis is maintained through distinct metabolic pathways in males and females. Cell-cell communication analysis showed that the same cellular state interaction network is linked to AD pathology through sex-biased ligand-receptor pairs. Disease association analyses further indicated that polygenic risk for AD is not uniformly distributed across cell states, but instead shows sex-biased enrichment in specific neuronal and glial circuits. Senescence analysis suggested that males and females exhibit distinct CS-specific signatures of cellular senescence in AD. Additionally, we identified oligodendrocytes MP13 and excitatory neuron MP1 as sex-biased meta-programs.
    CONCLUSIONS: Overall, our study identified sex-biased MPs across six major cell types and revealed that females displayed greater vulnerability to Aβ and tau pathology, while males carry a higher genetic risk burdens. These findings highlight cellular state heterogeneity underlying sex differences in AD.
    Keywords:  Alzheimer's disease; Cellular states; Sex difference; Single-cell RNA sequencing; Transcriptome meta-programs
    DOI:  https://doi.org/10.1186/s13195-026-02081-w
  43. Acta Neuropathol. 2026 May 15. pii: 55. [Epub ahead of print]151(1):
    Frequency of mixed neuropathologies in individuals with down syndrome with and without Alzheimer's dementia.
    Alzheimer’s Biomarker Consortium-Down syndrome (ABC-DS)
      Individuals with Down syndrome (DS) develop Alzheimer's disease neuropathological change (ADNC) by the age of 40 years, and most develop dementia by their early 50s. The frequency of co-pathologies in clinically and neuropathologically characterized adults with DS has not been systematically characterized. We characterized the frequency of ADNC and common co-pathologies, including cerebral amyloid angiopathy (CAA), Lewy pathology (LP), limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), hippocampal sclerosis (HS), and other cerebrovascular and macroscopic findings reported in standardized National Alzheimer's Coordinating Center (NACC) neuropathology forms in 63 adults with DS over 40 years. A secondary exploratory objective was to compare the neuropathological profiles between individuals with (n = 55) and without (n = 8) dementia from the same autopsy cohort. In the full autopsy cohort, cortical and hippocampal atrophy, and moderate-to-severe locus coeruleus hypopigmentation was a common finding. Pure ADNC, was present in only 29% of individuals. CAA was the most frequent co-pathology, present in approximately 84% of individuals followed by LP (21%), HS (19%), and LATE-NC (17%). Atherosclerosis and arteriolosclerosis were infrequent. In exploratory comparisons between dementia groups, brain weight was significantly lower in individuals with dementia than in those without (900 ± 116 vs 1060 ± 108 g P = .0006), and severe hippocampal atrophy and locus coeruleus hypopigmentation were more frequent in those with dementia (P = .049, P = .009, respectively). Advanced Braak NFT stage, frequent neuritic plaques, and high ADNC were more frequent in individuals with dementia (P = .0001, P = .03, P = .0016, respectively). LATE-NC and HS occurred exclusively in individuals with dementia, while LP and CAA were found in both groups. Individuals without dementia showed a less complex co-pathology profile than those with dementia. Our findings demonstrate that co-pathologies are present in people with DS, and that despite their genetic predisposition to AD, some individuals with DS may exhibit resilience and resistance mechanisms to AD.
    Keywords:  Cerebral amyloid angiopathy; Lewy pathology; Resilience and resistance to AD; TDP-43; Trisomy 21
    DOI:  https://doi.org/10.1007/s00401-026-03028-z
  44. Front Endocrinol (Lausanne). 2026 ;17 1738472
    TREM2 promotes adipogenesis of PDGFR-α+ adipose stem cells but is dispensable for adipose remodeling and metabolic health during diet-induced obesity.
    Anja Dobrijevic, Ana Korosec, Julia Stefanie Brunner, Lenka Matejovicova, Anna Gemza, Karin Lakovits, Hon Shing Lam, Aloña Agirre-Lizaso, Gernot Schabbauer, Sylvia Knapp, Omar Sharif.
      White adipose tissue (WAT) expands through adipocyte hypertrophy or hyperplasia-associated differentiation of progenitor adipose stem cells (ASC). The triggering receptor expressed on myeloid cells 2 (TREM2) reportedly promotes adipocyte differentiation and whole body TREM2 deletion in mice leads to adipose hypertrophy and worsened metabolic health. However, whether TREM2 expression in ASC is involved is unknown. Here, we find TREM2 is expressed on platelet derived growth factor receptor-α (PDGFR-α) positive ASC in obesity. While global deletion of TREM2 strongly attenuated adipocyte differentiation in three different cell culture models, conditional TREM2 deletion within PDGFR-α+ ASC impacted early adipocyte differentiation. Obese animals where TREM2 was specifically deleted in PDGFR-α+ expressing cells exhibited moderately increased ASC, but WAT morphology, macrophage amounts as well as glucose and insulin tolerance were comparable to littermate controls. Thus, although TREM2 is important for adipocyte differentiation in cell culture, its expression in ASC is dispensable for WAT remodeling and metabolic health during obesity.
    Keywords:  TREM2; adipogenesis; adipose stem cell; metabolic health; obesity; white adipose tissue
    DOI:  https://doi.org/10.3389/fendo.2026.1738472
  45. Int Immunopharmacol. 2026 May 11. pii: S1567-5769(26)00642-9. [Epub ahead of print]182 116796
    Andrograpanin attenuates secondary neuroinflammation after spinal cord injury by modulating microglial glycolysis via HIF-1α.
    Bin Dai, Xintian Ding, Kaichen Huang, Jiahao Ruan, Jiafeng Peng, Hongxing Zhang, Dapeng Li.
      Spinal cord injury (SCI), a devastating central nervous system disorder, often leads to persistent sensory, motor, and autonomic impairments that severely reduce quality of life. Following SCI, a rapidly formed hypoxic microenvironment induces abnormal accumulation of hypoxia-inducible factor-1α (HIF-1α), whose sustained activation triggers excessive pro-inflammatory cascades and dysregulated glycolysis, thereby aggravating secondary neuronal injury. In this study, we employed an integrated strategy combining network pharmacology, transcriptome sequencing, and in vivo and in vitro experiments to investigate the therapeutic potential of the Andrograpanin derivative Andrograpanin in SCI-induced secondary inflammation. Andrograpanin treatment significantly improved neurological function in SCI mice and prominently modulated HIF-1α expression along with downstream glycolysis-related genes. Mechanistic studies revealed that Andrograpanin directly inhibited HIF-1α transcriptional activity, reversing SCI-induced glycolytic hyperactivation, and regulated microglial polarization by shifting cells from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype, ultimately alleviating neuroinflammation. This intervention disrupted the hypoxia-driven, HIF-1α-mediated feedback loop that amplifies glycolysis and inflammation, thereby conferring neuroprotection. Collectively, our findings demonstrate that Andrograpanin exerts therapeutic effects in SCI by targeting HIF-1α to regulate glycolytic metabolism and microglial polarization, offering a novel immunometabolic strategy and valuable insights for future clinical translation.
    Keywords:  Andrograpanin; Glycolysis; Hypoxia-inducible factor-1α; Microglia; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.intimp.2026.116796
  46. Cells. 2026 May 02. pii: 835. [Epub ahead of print]15(9):
    Microglia in Epilepsy: From Molecular Mechanism to Therapeutic Strategy.
    Yam Nath Paudel, Efthalia Angelopoulou, Sai Kulkarni, Robert E Blair, Laxmikant S Deshpande.
      The limit of disease-modifying therapeutic strategies against epilepsy has prompted mainstream epilepsy research toward understanding the pathways contributing to epileptic seizures. Microglia, the powerhouse of the brain's innate immune system, is known for its role in epileptic seizures, contributing via neuroinflammation, neuronal death, and neurogenesis. Therapeutic targeting of microglia with its inhibitor and therapeutic compounds modulating its activation reduces the development of spontaneous recurrent seizure after status epilepticus in a pre-clinical model. Herein, we review various aspects of microglia in epilepsy, including their contribution to seizure-induced neuronal death and neurogenesis, the outcome of depleting microglia (both pharmacologically and genetically), the aspects of microglia-astrocyte interaction, and promising therapeutic outcomes achieved by targeting microglia.
    Keywords:  epilepsy; microglia; microglia depletion; minocycline; neurodegeneration; neurogenesis; seizure
    DOI:  https://doi.org/10.3390/cells15090835
  47. Nat Commun. 2026 May 12.
    Endothelial cell-secreted SPARC suppresses astrocytic CD59 expression and promotes astrocytopathy in a mouse model of neuromyelitis optica spectrum disorders.
    Tingting Cui, Ye Gong, Zhen Wang, Pei Li, Luhang Dai, Jia Chen, Zhe Feng, Xueli Liu, Shaogang Li, Huanyi Liu, Ke Li, Xiaoli Ding, Xiaochang Xue, Luting Yang, Lei Zhang, Rui Li, Ying Fu, Yaling Zhang, Yaping Yan.
      CD59 is an endogenous complement inhibitor that restricts membrane attack complex formation, protecting cells from complement-dependent cytotoxicity. Dysfunctional CD59 leads to uncontrolled complement activation and contributes to the pathogenesis of various diseases, including neuromyelitis optica spectrum disorder (NMOSD), a rare inflammatory autoimmune disorder specifically targeting astrocytes. However, the mechanisms underlying the regulation of CD59 expression are complex and need to be elucidated. Here, we show that in a clinically relevant NMOSD model using female mice, astrocytic CD59 protects astrocytes from AQP4-IgG and complement-mediated attacks. Through secretome and transcriptome analysis, we identified brain endothelial cell-derived SPARC as an inhibitor of VEGFA/VEGFR2 signaling, which suppresses astrocyte proliferation and CD59 production. Endothelial SPARC loss increases astrocytic CD59 and mitigates autoimmune astrocytopathy, whereas VEGFR2 activation induces CD59 and alleviates disease. Collectively, this study reveals how endothelial SPARC regulates astrocytic CD59 expression, promoting autoimmune astrocytopathy and providing a potential avenue for astrocyte-targeted therapies in NMOSD.
    DOI:  https://doi.org/10.1038/s41467-026-72997-2
  48. Sci Adv. 2026 May 15. 12(20): eaea0542
    Functional targeting of PTTG1 in pericytes restores vascular integrity in diabetic retina.
    Linyu Zhang, Ling Ren, Jingyue Zhang, Ya Zhao, Min Xia, Xiaosa Li, Mudi Yao, Fanfei Ma, Chang Jiang, Wan Mu, Jiao Xia, Jin Yao, Biao Yan.
      Pericyte loss is an early and critical event in the pathogenesis of diabetic retinopathy (DR), yet the molecular mechanisms underlying pericyte dysfunction remain incompletely understood. Using single-cell RNA sequencing, we generated a retinal cellular overview comprising 37,982 cells from diabetic and nondiabetic mice. We identified a previously unrecognized pericyte subpopulation defined by high expression of pituitary tumor-transforming gene 1 (Pttg1), which was enriched in diabetic retina. Functional studies demonstrated that CRISPR-Cas9- or small interfering RNA-mediated silencing of PTTG1 restored pericyte stability and barrier-supporting function under high-glucose stress. In vivo, Pttg1 silencing via viral or pericyte-specific adeno-associated virus delivery improved retinal vascular integrity and reduced retinal vascular dysfunction in diabetic mice. Integrated transcriptomic and metabolomic profiling revealed that PTTG1 silencing reprogrammed metabolism, modulating glycolytic flux and attenuating oxidative stress. Furthermore, a therapeutic strategy using spherical nucleic acid-based siPttg1 nanocarriers (sTDN-siPttg1) substantially ameliorated retinal vascular dysfunction in DR model. These findings suggest that PTTG1 is a critical regulator of pericyte metabolic homeostasis and microvascular function in DR, highlighting its translational potential as a therapeutic target for diabetic microvascular complications.
    DOI:  https://doi.org/10.1126/sciadv.aea0542
  49. Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2533968123
    Spatiotemporal control of PIWI compartmentalization by mitochondrial scaffolds defines pachytene piRNA pathway organization.
    Xiaoyuan Yan, Chao Wei, Jeffrey M Mann, Guanyi Shang, Qianyi Wang, Huirong Xie, Elena Y Demireva, Liangliang Sun, Deqiang Ding, Chen Chen.
      Pachytene piRNAs are the least understood class of piRNAs in the mammalian male germ line. During meiosis, their biogenesis occurs near the mitochondrial outer membrane in germ granules known as intermitochondrial cement (IMC). However, how mitochondrial factors regulate the trafficking of PIWI proteins into and out of the IMC remain poorly understood. Here we show that the cytoplasmic PIWI proteins MILI and MIWI are recruited for pachytene piRNA biogenesis via distinct mitochondrial membrane proteins. Loss of the mitochondrial scaffold protein ASZ1 during meiosis in mice disrupts multiple downstream biogenesis steps, resulting in misregulation of MILI, MIWI, and MOV10L1, failure of IMC formation, and an almost complete loss of mature pachytene piRNAs. Strikingly, despite the drastic depletion of pachytene piRNAs, LINE1 transposon silencing remains unaffected. We identify three classes of pachytene piRNA pathway components that coordinate piRNA production and compartmentalization. Our findings reveal that chromatoid body precursors serve as a central hub for the accumulation of pachytene PIWI-piRNA complexes, thus establishing a connection between IMC-based biogenesis and downstream piRNA function.
    Keywords:  ASZ1; PIWI; pachytene; piRNA; spermatogenesis
    DOI:  https://doi.org/10.1073/pnas.2533968123
  50. bioRxiv. 2026 Feb 24. pii: 2026.02.23.707321. [Epub ahead of print]
    Peripheral Metabolic Reprogramming Links TDP-43 Proteinopathy to Sleep Disruption.
    Anyara Rodriguez, Samuel J Belfer, Jenny Luong, Oksana Shcherbakova, Pinky Kain, Arjun Sengupta, Alexandra E Perlegos, Zhecheng Jin, Aalim M Weljie, Nancy M Bonini, Matthew S Kayser.
      Sleep disruption is an early and prevalent feature of neurodegenerative disease, commonly attributed to neuronal circuit dysfunction or cell loss. However, sleep is tightly coupled to metabolic state, raising the possibility that systemic metabolic abnormalities contribute to disease-associated sleep phenotypes. Using Drosophila models of TDP-43 proteinopathy, we investigated whether peripheral metabolic dysfunction plays a causal role in sleep disruption. We show that TDP-43 expression induces a chronic, starvation-like metabolic state characterized by depletion of peripheral carbohydrate and lipid stores despite normal feeding. Pharmacological restoration of sleep fails to correct these metabolic defects, whereas improving peripheral metabolic state through dietary or genetic interventions robustly rescues sleep. An RNAi-based modifier screen identifies Salt-inducible kinase 3 (SIK3) as a potent suppressor of both sleep loss and starvation sensitivity. Transcriptomic and spatial metabolomic analyses reveal that SIK3 selectively remodels a peripheral metabolic program centered on the pentose phosphate pathway and redox-associated metabolites without globally restoring energy stores. Together, these findings identify systemic metabolic dysfunction as a key driver of sleep disruption in TDP-43 proteinopathy and highlight peripheral metabolism as a potential therapeutic entry point for sleep dysfunction in neurodegenerative disease.
    DOI:  https://doi.org/10.64898/2026.02.23.707321
  51. J Physiol. 2026 May 15.
    Metabolic control of neuronal redox homeostasis: implications of pentose phosphate pathway loss in the nervous system.
    Samir Malick.
      
    Keywords:  NADPH metabolism; neurodegeneration; neuronal redox homeostasis; oxidative stress; pentose phosphate pathway
    DOI:  https://doi.org/10.1113/JP291385
  52. Mol Neurobiol. 2026 May 14. pii: 629. [Epub ahead of print]63(1):
    Comparative Analysis of Mouse CSF Proteins in Experimental Autoimmune Encephalomyelitis Model and Cuprizone-Induced Demyelination Model by Olink Proteomics.
    Eline Bernaerts, Marie Rutten, Amber De Visscher, Jarne Beliën, Nele Berghmans, Tania Mitera, Lien De Somer, Patrick Matthys, Jennifer Vandooren.
      Multiple sclerosis (MS) is marked by an autoimmune-driven inflammatory response within the central nervous system (CNS), resulting in demyelination and associated neurological impairment. To investigate the pathways involved in MS-related neuroinflammation, we performed cerebrospinal fluid (CSF) proteomic profiling (Olink®) across two murine models, i.e., the experimental autoimmune encephalomyelitis (EAE) and the cuprizone (CPZ)-induced demyelination models. Out of the 92 proteins analyzed, five (CCL2, CCL3, EDA2R, Fas, and HGF) were consistently dysregulated in both models, highlighting shared neuroinflammatory features alongside distinct pathological processes. In the EAE model, 31 proteins were upregulated compared to CPZ-intoxicated mice and controls and were mainly related to T cell development, effector functions and migration, reflecting the model's lymphocyte-centric nature. In contrast, the CPZ model showed a downregulation of a single protein, SEZ6L2, when compared to both EAE and controls. These findings emphasize the divergent protein profiles of CSF in EAE and CPZ models and underscore the different inflammatory pathways engaged in distinct pathophysiological mechanisms of MS.
    Keywords:  CSF proteins; Cuprizone-induced demyelination model; Experimental autoimmune encephalomyelitis model
    DOI:  https://doi.org/10.1007/s12035-026-05905-w
  53. Sci Adv. 2026 May 15. 12(20): eaea4183
    In situ structure of the human gap junction.
    Evans Eshriew, Esa-Pekka Kumpula, Shiv K Sah-Teli, Amiel Abettan, Amina Djurabekova, Vivek Sharma, Juha T Huiskonen.
      Gap junction plaques (GJPs) enable direct intercellular communication and consist of connexin channels arranged into two-dimensional lattices. While structures of purified connexin channels have informed models of gating, they omit key intracellular regions and lack native context. Here, we use cryo-electron tomography and focused ion beam milling to determine the in situ structure of human connexin 43 (Cx43) GJPs in HEK293 cells at 14-Å resolution. We reveal a previously unresolved structural contribution of the large carboxyl-terminal domain to lateral channel-channel interactions that appear critical for plaque assembly. Coarse-grained molecular dynamics simulations suggest how lipids and cholesterol occupy the space between adjacent connexins. These findings resolve a decades-old question regarding gap junction organization and highlight a mechanistic function for the carboxyl-terminal domain, likely regulated by a helix-loop-helix motif. Our study provides a structural blueprint for understanding how connexin diversity and regulation shape tissue-level communication in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.aea4183
  54. Nature. 2026 May 15.
    Mouse eyes photosynthesize after plant-to-animal transplant.
    Asher Mullard.
      
    Keywords:  Biotechnology; Cell biology; Plant sciences
    DOI:  https://doi.org/10.1038/d41586-026-01559-9
  55. Sci Rep. 2026 May 14.
    Generation of spinal cord organoids from human induced pluripotent stem cells caudalised to a lumbar fate.
    Li Jun Loh, Pratibha Panwar, Shila Ghazanfar, Kwaku Dad Abu-Bonsrah, Forough Habibollahi, Joel Mason, Brett J Kagan, Bradley J Turner, Samantha K Barton.
      Organoids offer a powerful platform to model human development and disease in vitro, while preserving key features of in vivo tissue architecture and complexity. In this study, we developed a protocol to generate human induced pluripotent stem cell (iPSC)-derived spinal cord organoids patterned to the lumbar region. Through immunofluorescent labelling and single-cell RNA sequencing analyses of these lumbar spinal cord organoids, we identified an enriched neuronal population complemented by a diverse array of glial subtypes that successfully recapitulate the ventral spinal cord, demonstrating greater anatomical relevance than conventional 2D motor neuron cultures. Notably, these organoids displayed functional neuronal properties, including spontaneous activity, indicative of integrated neural networks. This spinal cord organoid platform provides a physiologically relevant model for investigating human spinal cord development and presents a promising tool for studying neurodegenerative diseases and spinal cord injury in a controlled, human-specific context.
    Keywords:  Differentiation; Lumbar; Motor neurons; Organoid; Pluripotent stem cell; Spinal cord
    DOI:  https://doi.org/10.1038/s41598-026-45679-8
  56. Biochem Biophys Res Commun. 2026 Jul 09. pii: S0006-291X(26)00642-X. [Epub ahead of print]821 153878
    Macrophages are dispensable for taste bud regeneration upon nerve injury repair.
    Su Young Ki, Yong Taek Jeong.
      Peripheral sensory nerve injury triggers Wallerian degeneration, a process characterized by axonal fragmentation, myelin breakdown, and robust macrophage infiltration. While macrophages are widely implicated in debris clearance and repair within the injured nerve trunk, their functional role in the remodeling of sensory end organs remains poorly defined. Here, we investigated whether macrophages are required for taste bud degeneration and regeneration using a glossopharyngeal nerve transection model in mice. We first observed a marked accumulation of Iba1-positive macrophages in the circumvallate papilla after nerve injury, peaking at 2 weeks and coinciding with maximal taste bud loss. To test the functional requirement for these cells, we used both pharmacological and genetic depletion models. Despite near-complete depletion of infiltrating macrophages, the extent of taste bud loss at 2 weeks was indistinguishable from controls. Likewise, macrophage deficiency did not alter structural recovery at 4 weeks, with taste bud number, size, and the relative composition of different taste cell types remaining unchanged. These findings indicate that the major structural phases of taste bud degeneration and regeneration proceed despite macrophage depletion. Thus, although macrophage infiltration is a prominent feature of peripheral sensory denervation, it is not an essential driver of structural end-organ remodeling in the taste system.
    Keywords:  Macrophage; Nerve injury; Regeneration; Taste bud; Wallerian degeneration
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153878
  57. Nat Neurosci. 2026 May 14.
    Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.
    Ziyang Zhang, Lynn van Olst, Francesco Alessandrini, Matthew Wright, Alex J Edwards, Jake Boles, Anait Nalbandian, Anne V Forsyth, Nate Shepard, Thomas Watson, Evan Kaspi, Angeli Mittal, Joshua Kuruvilla, Natalie Piehl, Abhirami Ramakrishnan, Stanley Appel, Evangelos Kiskinis, David Gate.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron (MN) degeneration in the brain and spinal cord. Although neuroinflammation is increasingly recognized as a hallmark of ALS, the precise molecular programs linking immune responses to MN pathology remain poorly defined. Using an integrated approach that combines single-cell and bulk RNA sequencing with spatial proteogenomics, we characterized both shared and distinct immune dynamics in peripheral blood and spinal cord tissues from patients with sporadic ALS and those carrying C9orf72 repeat expansions. Our analysis revealed broad immune remodeling in C9orf72 ALS, ALS subtype-specific and progression-associated differences in monocyte activation and antigen-experienced CD8 effector memory T cells with clonal features consistent with antigen-driven responses. Spatial mapping revealed complement activation and lipid-programmed myeloid states converging at sites of MN loss and TDP-43 pathology. Together, these findings connect peripheral and central immune alterations to ALS heterogeneity and highlight stratified immunomodulation as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41593-026-02300-5
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