bims-micgli Biomed News
on Microglia
Issue of 2025–11–23
38 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.
  2. TREM2 Alleviates Neuroinflammation and Improves Neurogenesis in ApoE-/- Mice by Regulating M1/M2 Microglial Polarization.
  3. Chronic Intermittent Hypoxia Exposure Induces a Unique Microglial Transcriptome in 5XFAD Mice.
  4. Single-cell nanodroplet processing proteomics pipeline for analysis of human-derived microglia.
  5. Cathepsin B overexpression and lysosomal leakage in inflammatory microglia promote neuroinflammation in olfactory dysfunction by triggering mitochondrial dysfunction and pyroptosis.
  6. Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity.
  7. Author Correction: Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras.
  8. Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.
  9. Proteomic Profiling Reveals Mitochondrial Dysregulation in Rapidly Progressive Alzheimer's: Role of DLDH in Amyloid Beta Aggregation.
  10. Microglia across evolution: from conserved origins to functional divergence.
  11. Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy.
  12. Tau pathology in the brainstem monoaminergic neurons reflect resilience to Alzheimer's disease pathology in the Nun study cases.
  13. High Extracellular Glucose Concentration Drives Palmitate-Induced Toxicity and Metabolic Dysfunction in BV2 Microglia Cells.
  14. Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.
  15. High-sensitivity plasma proteomics reveals disease-specific signatures and predictive biomarkers of Alzheimer's disease phenotypes in a large mixed-dementia cohort.
  16. Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.
  17. Neuroinflammatory mechanisms linking high-fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis.
  18. Age-related inflammatory changes and perineuronal net dynamics: implications for aging.
  19. BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.
  20. Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.
  21. BACE1 Expression Is Required for Proper Synaptic Vesicle Dynamics in the Hippocampus.
  22. Polyinosinic Polycytidylic Acid (poly I:C) Induces Neuronal Cell Death Through NF-κB-Mediated Inflammation in Human Microglia and Neuroinflammation-Induced Cognitive Impairment in Mice.
  23. Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis.
  24. Progressive Loss of Astrocytic AIBP Expression during Alzheimer's Disease Pathology.
  25. Microglial colonization of the developing mouse brain is controlled by both microglial and neural CSF-1.
  26. C5aR1+ microglia exacerbate neuroinflammation and cerebral edema in acute brain injury.
  27. Microglial VRK2 Regulates Astrocytic GABA Synthesis and Tonic Inhibition in the Thalamus.
  28. Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-seq Data.
  29. Plexin-B1 safeguards astrocyte agility and glial alignment to facilitate wound corralling and axon pathfinding in mouse spinal cord injury model.
  30. Spatiotemporal mapping reveals Ccl8hi macrophages as key drivers of testicular inflammaging.
  31. Müller cell glutamine metabolism links photoreceptor and endothelial injury in diabetic retinopathy.
  32. Deficiency of SARM1 attenuates neuronal injury and improves neurological performance in a photothrombotic stroke model.
  33. Apolipoprotein E and Alzheimer's disease pathology in a diverse autopsy study.
  34. Proteome Signature of Alzheimer-Like Phenotypes in Frontal Cortices From Young and Old Individuals With Down Syndrome.
  35. Redirecting microglia phenotype via inhibition of NFAT1 ameliorates deficits in mouse model of synucleinopathies.
  36. Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice.
  37. The CSF Levels of Mitochondrial Phosphoenolpyruvate Carboxykinase 2 as a Novel Biomarker in Alzheimer's Disease.
  38. In situ amplification of α-synuclein amyloid fibril reveals a distinct polymorph related to Parkinson's disease and dementia with Lewy body.
  1. Alzheimers Dement. 2025 Nov;21(11): e70930
    Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.
    Morgan A Coburn, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Whitney England, Sepideh Kiani Shabestari, Kimiya Mansour, Amanda McQuade, Michael Armen Mgerian, Jean Paul Chadarevian, Christina Tu, Jorge Silva, Jaclyn Beck, Zahara Keulen, Robert C Spitale, Hayk Davtyan, Mathew Blurton-Jones.
       INTRODUCTION: Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear.
    METHODS: We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling.
    RESULTS: The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct "rod" morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro.
    DISCUSSION: We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.
    HIGHLIGHTS: Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.
    Keywords:  Alzheimer's disease; amyloid beta; human microglia; iPSC; rod microglia; tau; type I interferon
    DOI:  https://doi.org/10.1002/alz.70930
  2. Mol Neurobiol. 2025 Nov 20. 63(1): 105
    TREM2 Alleviates Neuroinflammation and Improves Neurogenesis in ApoE-/- Mice by Regulating M1/M2 Microglial Polarization.
    Xiao-Qian Peng, Zi-Kang Yang, Hong-Song Guo, Xiang-Yuan Wu, John Bosco Ruganzu, Zhong-Zhong Liu, Song-Di Wu, Wei-Na Yang.
      Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor abundantly expressed in microglia in the brain. Our previous study indicated that TREM2 promoted microglia polarization to the M2 phenotype in APP/PS1 transgenic mice and BV2 cells. It is reported that M2 microglia release brain-derived neurotrophic factor (BDNF) to enhance adult neurogenesis in the hippocampus. However, the role of TREM2 in hippocampal neurogenesis and the underlying mechanism are still less known. Apolipoprotein E knockout (ApoE-/-) mice exhibit cholinergic dysfunction, tau hyperphosphorylation, synaptic loss and dysfunction that may affect brain function and simulate Alzheimer's disease (AD). In this study, overexpression of TREM2 significantly increased the number of minichromosome maintenance 2 (MCM2) and doublecortin (DCX) cells in the subgranular zone (SGZ) of ApoE-/- mice. Additionally, the protein levels of MCM2 and DCX showed a similar trend. Furthermore, we found that overexpression of TREM2 promoted a phenotypical switch from M1 to M2 in microglia, as the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and CD86 were decreased, whereas the levels of IL-4, Arginase-1(Arg-1), BDNF, and CD206 were increased. Importantly, overexpression of TREM2 activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling pathways. In vitro, overexpression of TREM2 in primary microglia increased the production of anti-inflammatory factors (IL-4, Arg-1) and BDNF, while decreasing the production of pro-inflammatory factors (TNF-α, IL-1β). Furthermore, conditioned medium (CM) from TREM2 overexpressing primary microglia facilitated neural stem cells (NSCs) proliferation and differentiation into neurons. Moreover, the mechanistic study indicated that overexpression of TREM2 modulated microglial M2 polarization and promoted the proliferation and differentiation of NSCs partly via the PI3K/Akt and ERK1/2 signaling pathways. Collectively, these findings revealed that TREM2 may modulate microglial M2 polarization to inhibit neuroinflammation and increase the M2 microglia-derived BDNF to rescue hippocampal neurogenesis in ApoE-/- mice, and TREM2 can be considered a promising therapeutic factor to promote neurogenesis in AD and other brain diseases.
    Keywords:  Brain-derived neurotrophic factor; Hippocampal neurogenesis; Microglia; Neuroinflammation; Triggering receptor expressed on myeloid cells 2
    DOI:  https://doi.org/10.1007/s12035-025-05449-5
  3. Mol Neurobiol. 2025 Nov 19. 63(1): 81
    Chronic Intermittent Hypoxia Exposure Induces a Unique Microglial Transcriptome in 5XFAD Mice.
    Kaitlyn M Marino, Andrea C Ewald, Jaidynne N Lash, Erin C McCann, Shibani Ram, Phinea Z Romero, Tao Wang, Abigail L Watters, Abigail B Radcliff, Daniel C Shippy, Tracy L Baker, Tyler K Ulland, Jyoti J Watters.
      Clinical observations suggest that obstructive sleep apnea (OSA) and Alzheimer's disease (AD) pathology may be linked; however, causal mechanisms and relationships are unclear. To investigate the potential interaction between amyloidosis and intermittent hypoxia (IH), a hallmark of OSA, starting at 4 months of age 5XFAD mice were exposed to chronic IH (CIH) consisting of 20 episodes per hour of hypoxia for 12 h/day, daily for 4 months (males) or 6 months (females). CIH did not induce significant changes in amyloid burden or the number of astrocytes in males or females, but there was a slight decrease in the number of microglia observed in the cortex of 5XFAD mice of both sexes. To further explore this effect, we performed bulk RNA sequencing on isolated microglia. In WT mice, the most robust gene changes induced by CIH were identified in male microglia, many of which were pro-inflammatory. In microglia from 5XFAD mice, compared to normoxia (NX), CIH exposure induced comparatively more DEGs in males. Further, in genes that were upregulated by CIH in WT vs 5XFAD mice of both sexes, there was an enrichment of pathways associated with oxidative phosphorylation, aerobic and cellular respiration, and ATP synthesis. These changes indicate that CIH has a more robust effect on the microglial transcriptome in 5XFAD mice than in WT mice, suggesting that the synergy between AD and OSA pathologies may be driven by metabolic changes in the microglial transcriptome. These observations are particularly interesting given the known sex differences in OSA and AD pathology in human disease.
    Keywords:  Amyloid; Intermittent hypoxia; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1007/s12035-025-05390-7
  4. bioRxiv. 2025 Oct 04. pii: 2025.10.02.680067. [Epub ahead of print]
    Single-cell nanodroplet processing proteomics pipeline for analysis of human-derived microglia.
    Ashley N Ives, James M Fulcher, Alex R Bautista, Reta Birhanu Kitata, Sarah M Williams, David A Bennett, Philip L De Jager, Vladislav A Petyuk.
      Single-cell omics tools provide unique insights into heterogeneous cell populations and their responses to stimuli. For example, single-cell RNA sequencing has identified several transcriptionally distinct populations of microglia, which are resident immune cells of the central nervous system (CNS) that are responsive to CNS injury, infection, and neurodegeneration. To date, single cell studies of microglia have focused on RNA-sequencing or cytometry by time of flight (CyTOF) which provide indirect readouts of protein abundance or quantification of a limited number of targets. Herein, we present a workflow based on FACS-assisted isolation, cryopreservation and nanodroplet-based processing for single-cell mass spectrometry proteomics analysis of the postmortem human brain cortex-derived microglia. From a single microglial cell, 1039 proteins could be identified on average. As a proof-of-principle we applied single-cell proteomics for exploring the heterogeneity of brain microglia at the cellular level. This pilot proteomics data partially recapitulates the prior microglia subtypes. Specifically, we determined mitochondrial proteins, in particular members of NADH dehydrogenase (Complex I), cytochrome b-c1 (Complex III), cytochrome c oxidase (Complex IV), F1-ATPase (Complex V), and Na+/K+-ATPase complex drive variation across microglia. This pipeline offers the potential for identifying functionally and analytically relevant protein targets for microglia in Alzheimer's disease and other neurological disorders.
    Significance of Study: Microglia are a key brain cell type that may contribute to pathogenesis in neurodegenerative disease. Transcriptomic profiling of microglia from the central nervous system of humans and animal models has identified several subtypes of microglia, and complementary proteomic profiling of microglia is likely to provide functionally and therapeutically relevant targets, however single-proteomics studies of human-derived microglia are lacking. This work describes a label-free, single-cell proteomics approach for microglia isolated by fluorescence-activated cell sorting from a human donor that yields comparable numbers of identifications in comparison to prior single-cell RNA sequencing studies of microglia. This approach holds promise for enabling large-scale proteomics-based subtyping of microglia and studying their roles in neurodegenerative diseases.
    DOI:  https://doi.org/10.1101/2025.10.02.680067
  5. Brain Behav Immun. 2025 Nov 19. pii: S0889-1591(25)00430-1. [Epub ahead of print] 106188
    Cathepsin B overexpression and lysosomal leakage in inflammatory microglia promote neuroinflammation in olfactory dysfunction by triggering mitochondrial dysfunction and pyroptosis.
    Huiqin Zhou, Li Wang, Yuanyuan Yang, Fangzhou Ye, Xuanyu Zhao, Kesen Zhu, Huang Ziheng, Wei Lv, Hongmeng Yu.
      Olfactory dysfunction (OD) is a common sensory disorder with age-related prevalence and serves as an early clinical marker for neurodegenerative and inflammatory diseases. Microglia in the olfactory bulb (OB) rapidly respond to olfactory injury and initiate immune responses, but the cell state dynamics and pathways driving OD remain poorly understood. Here, we performed single-cell RNA sequencing of mouse OBs at 0, 7, and 30 days post olfactory injury, identifying 3 distinct microglial states including inflammatory, negative regulatory, and homeostatic.The inflammatory microglia exacerbated neuroinflammation by secreting cytokines and chemokines that recruited immune cells and amplify local immune responses. Cathepsin B was identified as a key regulator of this inflammatory microglial activity. In vitro studies using BV2 and primary microglia demonstrated that both pharmacological inhibition and genetic deletion of CTSB attenuated lipopolysaccharide (LPS)-induced mitochondrial dysfunction, NLRP3 activation, and pro-inflammatory cytokine release. In mice with OD, pharmacological inhibition of CTSB with CA074me promoted olfactory function recovery and modulated microglial pro-inflammatory responses. Our findings uncover inflammation-associated microglial subpopulations enriched in OD and suggest a deleterious role for CTSB-mediated neuroinflammatory signaling in OD pathogenesis. Targeting CTSB may represent a promising therapeutic strategy to mitigate microglia-mediated neuroinflammation and facilitate olfactory recovery in OD. Olfactory dysfunction (OD) is a common sensory disorder with age-related prevalence and serves as an early clinical marker for neurodegenerative and inflammatory diseases. Microglia in the olfactory bulb (OB) rapidly respond to olfactory injury and initiate immune responses, but the cell state dynamics and pathways driving OD remain poorly understood. Here, we performed single-cell RNA sequencing of mouse OBs at 0, 7, and 30 days post olfactory injury, identifying 3 distinct microglial states including inflammatory, negative regulatory, and homeostatic. The inflammatory microglia exacerbated neuroinflammation by secreting cytokines and chemokines that recruited immune cells and amplify local immune responses. Cathepsin B was identified as a key regulator of this inflammatory microglial activity. In vitro studies using BV2 microglia demonstrated that both pharmacological inhibition and genetic deletion of CTSB attenuated lipopolysaccharide (LPS)-induced mitochondrial dysfunction, NLRP3 activation, and pro-inflammatory cytokine release. In mice with OD, pharmacological inhibition of CTSB with CA074me promoted olfactory function recovery and modulated microglial pro-inflammatory responses. Our findings uncover inflammation-associated microglial subpopulations enriched in OD and suggest a deleterious role for CTSB-mediated neuroinflammatory signaling in OD pathogenesis. Targeting CTSB may represent a promising therapeutic strategy to mitigate microglia-mediated neuroinflammation and facilitate olfactory recovery in OD.
    Keywords:  Cathepsin B; Inflammatory response; Microglia; Neuroinflammation; Olfactory bulb; Olfactory dysfunction; Pyroptosis
    DOI:  https://doi.org/10.1016/j.bbi.2025.106188
  6. Nat Commun. 2025 Nov 21. 16(1): 10285
    Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity.
    Samuel J Resnick, Seema Qamar, Pushya Krishna, Vladislav Korobeynikov, Hannes Ausserwoger, Alyssa Miller, Pietro Esposito, Juan A Varela, Jenny Sheng, Lei Haley Huang, Jonathon Nixon-Abell, Schuyler Melore, Chyi Wei Chung, Nino F Läubli, Sofia Kapsiani, Xuecong Li, Jingshu Wang, Nancy Zhang, Mahabub Maraj Alam, Alondra S Burguete, Theresa C Swayne, Yanyan Chen, Ya-Cheng Liao, Neil A Shneider, Michele Vendruscolo, Tuomas P J Knowles, Clemens F Kaminski, Francesco Simone Ruggeri, Gabriele S Kaminski Schierle, Peter St George-Hyslop, Alejandro Chavez.
      Neurodegenerative disorders (NDDs) are a family of diseases that remain poorly treated despite their growing global health burden. To gain insight into the mechanisms and modulators of neurodegeneration, we developed a yeast-based multiplex genetic screening platform. Using this platform, 32 NDD-associated proteins are probed against a library of 132 molecular chaperones from both yeast and humans, and an unbiased set of ~900 human proteins. We identify both broadly active and specific modifiers of our various cellular models. To illustrate the translatability of this platform, we extensively characterize a potent hit from our screens, the human chaperone DNAJB6. We show that DNAJB6 modifies the toxicity and solubility of multiple amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)-linked RNA-binding proteins (RBPs). Biophysical examination of DNAJB6 demonstrated that it co-phase separates with, and alters the behavior of FUS containing condensates by locking them into a loose gel-like state which prevents their fibrilization. Domain mapping and a deep mutational scan of DNAJB6 revealed key residues required for its activity and identified variants with enhanced activity. Finally, we show that overexpression of DNAJB6 prevents motor neuron loss and the associated microglia activation in a mouse model of FUS-ALS.
    DOI:  https://doi.org/10.1038/s41467-025-65178-0
  7. Nat Commun. 2025 Nov 18. 16(1): 10066
    Author Correction: Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras.
    Youqiao Wang, Zeyi Wang, Ziyi Liu, Jinyan Li, Shuo Yang, Yuxuan Zhao, Yangmei Huang, Chenyang Liao, Yiqiu Zhang, Jiaojiao Zhao, Weilin Zhou, Binhua Zhou, Xin Yue, Qiang Zhou, Xianzhang Bu.
      
    DOI:  https://doi.org/10.1038/s41467-025-66496-z
  8. Alzheimers Res Ther. 2025 Nov 20. 17(1): 248
    Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.
    Hayato Etani, Sho Takatori, Wenbo Wang, Jumpei Omi, Yusuke Amiya, Aika Akahori, Hirotaka Watanabe, Iki Sonn, Hideyuki Okano, Norikazu Hara, Mai Hasegawa, Akinori Miyashita, Masataka Kikuchi, Takeshi Ikeuchi, Maho Morishima, Yuko Saito, Shigeo Murayama, Takashi Saito, Takaomi C Saido, Toshiyuki Takai, Tomohiko Ohwada, Junken Aoki, Taisuke Tomita.
       BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood.
    METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets.
    RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice.
    CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.
    Keywords:  Alzheimer disease; Amyloid-β; GPCR; GPR34; Microglia; Phagocytosis; Single-nucleus RNA sequencing; Therapeutic target
    DOI:  https://doi.org/10.1186/s13195-025-01891-8
  9. Mol Neurobiol. 2025 Nov 19. 63(1): 73
    Proteomic Profiling Reveals Mitochondrial Dysregulation in Rapidly Progressive Alzheimer's: Role of DLDH in Amyloid Beta Aggregation.
    Saima Zafar, Aneeqa Noor, Neelam Younas, Mohsin Shafiq, Kathrin Dittmar, Oleksandr Yagensky, Matthias Schmitz, Isidre Ferrer, Peter Hermann, Inga Zerr.
      Alzheimer's disease (AD) is presented as multiple clinical variants depending upon the rate of progression and familial background; however, the exact molecular mechanisms associated with these subtypes and their treatments are yet to be understood. The current study is based on a global proteome analysis of brain samples from patients (n = 38) with rapidly progressive AD (rpAD-survival time < 3 years), sporadic AD (spAD-survival time of 8-10 years), and healthy controls. Proteome analysis revealed a differential regulation of 79 proteins and highlighted the dysregulation of mitochondrial machinery and glucose metabolism in rpAD. Dihydrolipoamide dehydrogenase (DLDH), a mitochondrial oxidoreductase, showed a significant reduction and delocalization in rpAD. In vitro analysis revealed a potential role of DLDH in the aggregation of amyloid beta. Rapid progression in AD may be influenced by the energy homeostasis and redox dysfunction linked with the DLDH.
    Keywords:  Alzheimer’s disease (AD); DLDH; Metabolic networks; Metabolism; Post-translational modification; Proteomics; Rapidly progressive Alzheimer’s disease (rpAD)
    DOI:  https://doi.org/10.1007/s12035-025-05327-0
  10. Cell Mol Immunol. 2025 Nov 21.
    Microglia across evolution: from conserved origins to functional divergence.
    Takashi Shimizu, Marco Prinz.
      Microglia, the resident immune cells of the central nervous system, exhibit conserved developmental origins and core molecular signatures across vertebrate species, highlighting their crucial importance in the central nervous system. While homeostatic microglia maintain similar functions during phylogeny-such as immune surveillance, debris clearance, and synaptic pruning-their morphology, gene expression, and responses to stimuli remarkably vary by species. These differences reflect evolutionary divergence shaped by factors such as lifespan, regenerative potential, and immune architecture. This review integrates current findings from basic vertebrates such as zebrafish, rodents, and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution. Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.
    Keywords:  Microglia; evolution; ontogeny; species
    DOI:  https://doi.org/10.1038/s41423-025-01368-6
  11. Acta Neuropathol. 2025 Nov 20. 150(1): 54
    Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy.
    Shahar Hartman, Nurgul Aytan, Raymond Nicks, Samantha Hawkins, Jonathan Cherry, Victor E Alvarez, Gaoyuan Meng, Yorghos Tripodis, Brett Martin, Joseph Palmisano, Lee E Goldstein, Douglas I Katz, Brigid Dwyer, Daniel H Daneshvar, John F Crary, Michael Alosco, Weiming Xia, Ann C McKee, Jesse Mez, Thor D Stein.
      Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common Transmembrane Protein 106B (TMEM106B) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether TMEM106B alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype (rs3173615). We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between TMEM106B risk and CTE presence, CTE stage, TDP-43, and dementia in those < = 65 and > 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by TMEM106B genotype. Among donors > 65 years old, the TMEM106B risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183-6.383], p = 0.019), comparable to the effect of playing > 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278-10.422], p = 0.016). In donors < = 65, TMEM106B risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015-23.705], p = 0.002). TMEM106B gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 (p's < 0.05), and TNF-α was negatively associated with cortical tau (p = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the TMEM106B risk genotype in CTE. Overall, TMEM106B rs3173615 is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.
    Keywords:  CTE; Cytokines; Microglia; Neuropathology; RHI; TMEM106B
    DOI:  https://doi.org/10.1007/s00401-025-02955-7
  12. Acta Neuropathol Commun. 2025 Nov 19. 13(1): 239
    Tau pathology in the brainstem monoaminergic neurons reflect resilience to Alzheimer's disease pathology in the Nun study cases.
    Maryam Kherad Pezhouh, Gang Chen, Joyce Meints, Laura S Hemmy, Karen S SantaCruz, Michael K Lee.
      The presence of amyloid and tau pathologies is the pathological hallmark of Alzheimer's disease (AD). However, the presence of non-demented individuals with sufficient AD pathology indicates that AD-linked pathology does not always lead to dementia. The current view is that a non-demented (ND) individual with sufficient AD pathology represents an individual resilient to AD pathology. To gain insight about resilience to AD pathology, we examined the neuropathology in the brainstem monoaminergic (MAergic) neurons in the Nun Study participants with equally high Braak AD stage (V-VI) with dementia and without clinical dementia. Because MAergic pathology is thought to occur in response to cortical AD pathology, any differences in MAergic pathology between the AD and ND groups with similarly advanced AD pathology could reflect the resilience of MAergic neurons to cortical AD pathology. Examination of Locus Coeruleus (LC) and/or Raphe for the presence of tau pathology showed that, despite the similar forebrain pathology, relative levels of perikaryal and neuritic tau pathology were significantly lower in ND than in AD subjects. The ND subjects exhibit greater pathology than control subjects without AD pathology, indicating that cortical AD pathology does impact subcortical neurons in both AD and ND cases. Significantly, the extent of neurodegenerative pathology in LC and Raphe neurons correlated with cognitive performance in AD cases, while no such correlation was seen in ND cases. Our results show that while cortical AD pathology is associated with increased MAergic neuropathology, quantitative differences in the extent of MAergic pathology in the brainstem may reflect underlying resistance to AD pathology.
    Keywords:   Cognitive reserve; Alzheimer’s disease; Brain reserve; Brainstem; Locus coeruleus; Raphe
    DOI:  https://doi.org/10.1186/s40478-025-02167-w
  13. Mol Neurobiol. 2025 Nov 21. 63(1): 118
    High Extracellular Glucose Concentration Drives Palmitate-Induced Toxicity and Metabolic Dysfunction in BV2 Microglia Cells.
    Wembley Rodrigues Vilela, Nicolle Platt, Luiz Roberto Grassmann Bechara, Gabriela Cristina de Paula, Julio Cesar Batista Ferreira, Jade de Oliveira, João M N Duarte, Andreza F de Bem.
      Microglia exhibit targeted responses to different stimuli, including lipids, which can differ depending on the environmental conditions they encounter. These responses involve inflammatory mediators and are crucial for maintaining brain homeostasis. This study investigated whether inflammatory, metabolic, and phagocytic responses of microglia to the saturated fatty acid palmitate depend on extracellular glucose concentrations. BV2 microglial cells were cultured in low glucose (LG; 5.5 mmol/L) or high glucose (HG; 25 mmol/L) concentrations, and then exposed to palmitate (100 or 200 µmol/L) or vehicle for 24 h. Under HG, palmitate decreased cell viability, which was accompanied by an increase in inflammatory markers, which are associated with an activated state. Additionally, palmitate induced higher expression of genes related to lipid metabolism in both LG and HG, without affecting enzymes linked to glucose metabolism. HG condition led to an increase in the oxygen consumption rate (OCR) and glycolytic flux (i.e., extracellular medium acidification) compared to LG-cultured cells, with palmitate reducing OCR and glycolytic flux in both conditions. The short-chain fatty acid butyrate did not prevent palmitate-induced mitochondrial dysfunction in BV2 cells. In primary microglia, palmitate did not affect mitochondria density and cargo metabolism. Altogether, our results indicate that BV2 cells are prone to palmitate-induced stress on viability assays under HG but not LG in the medium.
    Keywords:  Glucolipotoxicity; Microglia; Mitochondria; Palmitate; Phagocytosis
    DOI:  https://doi.org/10.1007/s12035-025-05455-7
  14. J Neuroinflammation. 2025 Nov 15. 22(1): 272
    Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.
    Francesca Sironi, Massimo Tortarolo, Sabrina Mazzucchi, Laura Camporeale, Mattia Freschi, Eliana Arcadipane, Giulia De Giovanetti, Mami Kurosaki, Mineko Terao, Paola Parlanti, Paola Podini, Francesco Gentile, Valentina Bonetto, Valentina Cappello, Nilo Riva, Angelo Quattrini, Caterina Bendotti.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder where neuromuscular health is central to disease progression. The degeneration of motor neurons (MNs) leads to muscle weakness and paralysis, underscoring the critical importance of neuromuscular junctions (NMJs) and axonal integrity. Among the genetic contributors to ALS, mutations in the C9orf72 gene are the most common, accounting for both ALS and frontotemporal dementia (FTD). While the role of C9orf72 has been studied across various cells and compartments, its function in the peripheral nervous system (PNS), a compartment crucial for maintaining neuromuscular connectivity in ALS,remains largely unexplored.
    MAIN BODY: Our study investigates the role of C9orf72 loss-of-function in ALS, focusing on its neuromuscular effects. C9orf72 expression is localized in MNs, microglia, oligodendrocytes, and Schwann cells (SCs) in the sciatic nerve (SN), but not in astrocytes. The absence of C9orf72 in mice is associated with hypomyelination and axonal sorting defect in the SN, but not with MNs loss in lumbar spinal cord. Additionally, we identified immune dysregulation, with elevated CD8+ T cells transcript and increased major histocompatibility complex I (MHCI) expression in SCs, in association with enhanced NMJ denervation in C9orf72-deficient ALS mice, suggesting a potential contribution of immune dysregulation to disease progression. These changes contributed to NMJ denervation characterized by increase in the expression of acetylcholine receptor gamma (AChRγ). The combination of C9orf72-deficiency with the ALS-linked SOD1G93A mutation resulted in a more severe phenotype and accelerated disease progression, despite no additional spinal MN loss.
    CONCLUSION: Our findings underscore the critical role of C9orf72 in maintaining neuromuscular health through its influence on myelination, immune response regulation, and NMJ integrity. Loss of C9orf72 function exacerbates ALS progression by promoting SC dysfunction and immune dysregulation. This highlights the significance of preserving normal C9orf72 function in ALS therapies through antisense oligonucleotides strategies. Furthermore, targeting immune responses and myelination pathways may offer novel avenues for ALS treatment strategies.
    Keywords:  Amyotrophic lateral sclerosis; C9orf72; Immune system; Peripheral nervous system; SOD1G93A mice
    DOI:  https://doi.org/10.1186/s12974-025-03597-y
  15. Mol Neurodegener. 2025 Nov 17. 20(1): 120
    High-sensitivity plasma proteomics reveals disease-specific signatures and predictive biomarkers of Alzheimer's disease phenotypes in a large mixed-dementia cohort.
    Katherine Gong, Jigyasha Timsina, Muhammad Ali, Yike Chen, Menghan Liu, Ciyang Wang, Cyril Pottier, Geoffrey K Feld, Gyujin Heo, Tammie L S Benzinger, Cyrus A Raji, Beau Ances, Brian A Gordon, Julie K Wisch, Suzanne E Schindler, John C Morris, David M Holtzman, Laura Ibanez, Carlos Cruchaga.
      Novel plasma assays enabled accurate blood-based biomarkers for neurodegenerative diseases with minimally invasive options for clinical use. Large-scale studies encompassing multiple neurodegenerative diseases using novel multiplex platforms are essential to uncover disease-specific biomarkers and pathways. We generated and analyzed plasma biomarker data using the NULISAseq™ CNS Panel from 3,232 participants with Alzheimer disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), Parkinson disease (PD) and cognitively unimpaired individuals, from the Charles F. and Joanne Knight Alzheimer Disease Research Center. We identified proteins associated with disease status and AD-related phenotypes (Clinical Dementia Rating®, CSF Aβ42/Aβ40, Amyloid-PET, and Tau-PET). These proteins were used to identify disease-specific biomarkers and perform pathway analyses. We identified 81 proteins associated with AD, 21 with DLB, four with FTD, and 52 with PD after multiple test correction. Disease comparison showed that PD and DLB had the highest similarity, followed by AD and DLB. Concurrently, each disease also presented disease-specific signatures. Some AD-specific proteins included p-tau217; MSLN and SAA1 were specific to DLB, and FLT1 and PARK7 to PD. We also identified eight proteins associated with Amyloid-PET, eight with Tau-PET, 14 with CSF Aβ42/40 ratio, and 72 with CDR, some of which were specific to each phenotype. We used a data-driven approach to identify the p-tau217 cut-off for biomarker positivity. Plasma p-tau217 achieved an AUC of 0.81 (95% CI: 0.79-0.83) for AD diagnosis and 0.96 (95% CI: 0.94-0.98) for Amyloid positivity. P-tau217 had 93.77% agreement with Amyloid-PET status. Proteins associated with AD were enriched in protein-lipid complex binding pathway, whereas PD associated proteins were enriched in laminin-related pathways. FTD associated proteins were enriched in cytoskeleton proteins. This is the largest plasma NULISA CNS study performed till date and covers the four major neurodegenerative diseases: AD, PD, DLB and FTD. We validated the high classification accuracy of the NULISA plasma p-tau217 and its strong correlation with Amyloid-PET status. We also identified disease-specific proteins that could enhance differential diagnosis. These findings highlight the potential of the NULISA platform as a reliable quantitative tool for research and clinical applications in neurodegenerative diseases.
    Keywords:  CNS protein profiling; Neurodegeneration diagnostics; Plasma assays; Plasma-based diagnostics
    DOI:  https://doi.org/10.1186/s13024-025-00909-x
  16. J Neurochem. 2025 Nov;169(11): e70304
    Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.
    Emil W Westi, Rebecca Birch Carlsen, Jens Velde Andersen, Zeliha Kilic, Dana Alnajar, Nadia K Holmgaard, Belén García Sintes, Agustin Cota-Coronado, Sonia Sanz Muñoz, Céline Galvagnion, Blanca I Aldana.
      Microglia, the main resident immune cells of the brain, play critical roles in maintaining neuronal function and homeostasis. Microglia's metabolic flexibility enables rapid adaptation to environmental changes, yet the full extent of their metabolic capabilities and influence on neuronal metabolism remains unclear. While microglia predominantly rely on glucose oxidative metabolism under homeostatic conditions, they shift towards glycolysis upon proinflammatory activation. In this study, we investigated microglial metabolism and its impact on neuronal metabolic homeostasis using isotope tracing with stable carbon 13C-enriched substrates and gas chromatography-mass spectrometry (GC-MS) analysis. Primary microglia were incubated with 13C-labeled glucose, glutamine, or GABA in the presence or absence of lipopolysaccharide (LPS) to assess metabolic adaptations upon an inflammatory challenge. Additionally, neurons co-cultured with quiescent or activated microglia (either with LPS or amyloid-β) were incubated with 13C-enriched glucose to examine microglia-neuron metabolic interactions. Our findings confirm that microglia readily metabolize glucose and glutamine, with LPS stimulation slightly changing the glycolytic activity, as indicated by subtle changes in extracellular lactate. Importantly, we demonstrate for the first time that microglia take up and metabolize the inhibitory neurotransmitter GABA, suggesting a novel metabolic function. Furthermore, microglial presence directly influences neuronal metabolism and neurotransmitter homeostasis, highlighting a previously unrecognized aspect of neuron-microglia metabolic crosstalk. Collectively, these findings provide new insights into microglial metabolism and its role in neuronal function, with implications for neuroinflammatory and neurodegenerative diseases in which microglial metabolism is dysregulated.
    Keywords:  GABA metabolism; amyloid‐beta; glutamine; metabolic flexibility; neuroimmune interactions; neurons
    DOI:  https://doi.org/10.1111/jnc.70304
  17. Alzheimers Dement. 2025 Nov;21(11): e70911
    Neuroinflammatory mechanisms linking high-fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis.
    Sabrina E Mackey-Alfonso, Ruth M Barrientos.
      As global life expectancy increases, Alzheimer's disease (AD) incidence is rising rapidly. While research has long focused on amyloid beta (Aβ) and tau pathology, recent controversies and limited clinical success of Aβ-targeting therapies have challenged their centrality in AD. Emerging evidence highlights neuroinflammation as an earlier and potentially more critical driver of disease, particularly in response to environmental and lifestyle factors. High saturated fat diets (HFD) are strongly associated with increased AD risk in both clinical and preclinical studies. This review examines how HFD promotes AD vulnerability via neuroinflammatory mechanisms, including toll-like receptor 4 activation and complement system overactivation, which contribute to synaptic loss and cognitive decline-often independent of Aβ burden and metabolic dysfunction. Short-term HFD exposure can rapidly induce neuroinflammation and impair memory, underscoring the direct impact of diet on brain health. These insights support a shift toward targeting immune pathways and synaptic preservation in AD prevention and treatment. HIGHLIGHTS: High saturated fat diets (HFDs) increases Alzheimer's disease risk independently of obesity or insulin resistance. Neuroinflammation is a key driver of HFD-induced cognitive decline. Toll-like receptor 4 (TLR4) activation links saturated fats to synaptic loss and memory deficits. HFDs promote complement-mediated microglial synaptic engulfment. Short-term HFD exposure rapidly impairs memory and increases brain inflammation.
    Keywords:  Alzheimer's disease; complement system; high‐fat diet; neuroinflammation; synaptic loss; toll‐like receptor 4
    DOI:  https://doi.org/10.1002/alz.70911
  18. J Neuroinflammation. 2025 Nov 18. 22(1): 274
    Age-related inflammatory changes and perineuronal net dynamics: implications for aging.
    Zachary A Colon, Shannon C Chan, Kathleen A Maguire-Zeiss.
       BACKGROUND: Healthy aging alone can lead to cognitive decline, decreased brain size, protein aggregation, accumulation of senescent cells and neuroinflammation. Furthermore, age is the primary risk factor for several neurodegenerative disorders such as Parkinson's and Alzheimer's disease. Age-related neuroinflammation, as known as inflammaging, is thought to restrict brain plasticity. Perineuronal nets (PNNs), specialized extracellular matrix structures surrounding fast-spiking parvalbumin (PV) interneurons, regulate plasticity and protect neurons from oxidative stress. Given the known impact of inflammaging on neural circuits, this study examines age-associated changes in PNN homeostasis, glial activation, and neuroinflammation in two brain regions relevant to age-related neurodegenerative diseases.
    METHODS: We analyzed young (4-month-old) and aged (22-month-old) C57BL/6J male mice for several behavioral phenotypes [hippocampal-dependent spatial learning using the Barnes maze; locomotion and anxiety-related behaviors using Open field and T-maze]. Using immunostaining, PNNs (Wisteria floribunda agglutinin and aggrecan), PV interneurons, and microglial activation (Iba1) were quantified in both the hippocampus and dorsal striatum. Glial morphology was examined using a battery of cell body, branching, and endpoint analyses. Quantitative RT-PCR was used to analyze changes in the gene expression of inflammatory and extracellular matrix markers.
    RESULTS: Aged mice exhibited hippocampal-dependent memory deficits without alterations in locomotion or anxiety-related behavior. PNN counts increased in the aged hippocampus, particularly in CA2, with a higher proportion of WFA+ and aggrecan+ PNNs. In contrast, PNN homeostasis was maintained in the dorsal striatum. In general, Aged mice showed increases in microglial activation and a subset of inflammatory markers. We report brain region- and age- specific gene expression changes in complement, matrix metalloproteinases, and other inflammatory markers. Aged striatal microglia displayed an activated morphology with larger cell bodies and reduced branching, as well as increased expression of markers for microgliosis (Iba1, TREM2, CD68).
    CONCLUSIONS: These findings suggest that aging differentially affects neuroinflammation and PNN integrity across brain regions. The hippocampus exhibits PNN accumulation, neuroinflammation, and behavioral changes, whereas the striatum maintains PNN homeostasis concurrent with increased microglial activation. This work suggests that neuroinflammation contributes to age-related changes in PNNs and behavior underscoring the importance of region-specific therapeutic strategies targeting PNN regulation.
    Keywords:  Hippocampus; Inflammaging; Neuroinflammation; Parvalbumin; Striatum
    DOI:  https://doi.org/10.1186/s12974-025-03568-3
  19. EMBO Rep. 2025 Nov 20.
    BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.
    Hannah Heininger, Xiao Feng, Alp Altunkaya, Fang Zheng, Florian Stockinger, Benedikt Wefers, Stephan A Müller, Pieter Giesbertz, Sarah K Tschirner, Dorina Shqau, Helmuth Adelsberger, Alexey Ponomarenko, Thomas Fenzl, Christian Alzheimer, Stefan F Lichtenthaler, Tobias Huth.
      The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.
    Keywords:  BACE1; EEG; Non-Enzymatic; Power Spectrum; Sleep-Wake Cycle
    DOI:  https://doi.org/10.1038/s44319-025-00604-4
  20. Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2505046122
    Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.
    Firoz Akhter, Asma Akhter, Xiongwei Zhu, Hillary Schiff, Arianna Maffei, Justin T Douglas, Qifa Zhou, Zhen Zhao, Donghui Zhu.
      Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimer's-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gAβ-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.
    Keywords:  Alzheimer’s disease; glycated amyloid-beta; innate immunity; mitochondrial DNA
    DOI:  https://doi.org/10.1073/pnas.2505046122
  21. J Neurochem. 2025 Nov;169(11): e70299
    BACE1 Expression Is Required for Proper Synaptic Vesicle Dynamics in the Hippocampus.
    John Zhou, Srdjan D Antic, Brati Das, Wanxia He, Dang Minh Tran, Xiangyu Hu, Rafael Fernández-Chacón, Riqiang Yan.
      BACE1 is an indispensable enzyme for the production of β-amyloid peptides by initiating the cleavage of amyloid precursor protein at the β-secretase site. Targeting BACE1 inhibition is therefore a therapeutic strategy for treating patients with Alzheimer's disease. However, several clinical trials using brain-penetrable BACE1 inhibitors have failed due to a lack of efficacy. Previous studies, including our own, have shown that both global and neuron-specific BACE1 inhibition in mice leads to impairments in synaptic strength and spine density. In this study, we investigate the effects of BACE1 inhibition on activity-dependent synaptic vesicle exocytosis and endocytosis using a synapto-pHluorin mouse model. Our results demonstrate impaired synaptic release in BACE1-deficient mice. Furthermore, transcriptomic analysis reveals a significant downregulation of genes related to synapse structure and function. Pathway analysis suggests that BACE1 deficiency significantly downregulates neurexin-neuroligin pathway, which can modulate docking and release of synaptic vesicles at the presynaptic compartment. Our findings suggest that BACE1 inhibition may lead to deficits in synaptic vesicle exocytosis due to the downregulation of key synaptic proteins.
    Keywords:  BACE1; synaptic plasticity; synaptic vesicles; synapto‐pHluorin; transcriptomic analysis
    DOI:  https://doi.org/10.1111/jnc.70299
  22. Mol Neurobiol. 2025 Nov 19. 63(1): 82
    Polyinosinic Polycytidylic Acid (poly I:C) Induces Neuronal Cell Death Through NF-κB-Mediated Inflammation in Human Microglia and Neuroinflammation-Induced Cognitive Impairment in Mice.
    Aseel Y Altahrawi, Antonisamy William James, Zahoor A Shah.
      Neuroinflammation and neuronal death are direct consequences of persistent microglial activation, a phenomenon observed in many chronic neurological conditions. Activated microglia impact neuronal cells by releasing proinflammatory cytokines and inflammatory mediators, leading to neuronal damage and neurodegeneration. To investigate whether polyinosinic polycytidylic acid (poly I:C), a synthetic double-stranded RNA molecule, induces neuroinflammation and neuronal death, we exposed human microglia (HMC-3 cells) to poly I:C for 24 h, and performed inflammatory cytokine analysis. Additionally, to investigate whether poly (I:C) induces memory impairment and motor coordination deficits in mice, we conducted a behavioral assessment and also measured the expression of inflammatory cytokines in the brain. Poly (I:C) exposure significantly increased the mRNA and protein expression of inflammasome, proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-8, IL-12, and IL-18) and chemokines in microglia. Poly (I:C) also significantly increased the translocation of NF-kB from the cytosol to the nucleus. Furthermore, the conditioned medium from poly (I:C)-treated cells markedly increased apoptosis in human neuronal cells (differentiated SHSY5Y cells) by activating pro-apoptotic markers, including Bax, Bad, cleaved caspase-3, cleaved PARP, and AIF. Mice exposed to poly (I:C) showed a significant increase in mRNA expression of inflammatory cytokines, such as IL-6 and TNF-α, in the hippocampus. A decrease in the percentage of alternation on the T-maze, reduced distance travelled, and average speed in the open field test indicate cognitive deficits as well as anxiety-like behavior in mice exposed to poly (I:C). These findings suggest that poly (I:C) induces neuroinflammation through the inflammasome and proinflammatory mediators via the NLRP3/NF-κB signaling pathway in vitro and in vivo.
    Keywords:  Memory impairment; Neuroinflammation; Neuronal death; Poly (I:C); Proinflammatory cytokines
    DOI:  https://doi.org/10.1007/s12035-025-05299-1
  23. Nat Commun. 2025 Nov 21.
    Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis.
    Kylie Klinkhammer, Rachel Warren, Joseph Knopp, Toan Nguyen, Stijn P De Langhe.
      The coordination between epithelial progenitors and their mesenchymal niche is critical for organogenesis and repair, yet the mechanisms governing their competitive interactions remain unclear. Here, we reveal a paradigm of tissue-scale fitness sensing in the lung, where mesenchymal Yap levels antagonize epithelial Yap levels to dictate epithelial stem cell fate. We show that reduced fitness in alveolar fibroblasts (AF1s) via Yap/Taz or Myc deletion leads to their apoptotic elimination and a collapse of the alveolar stem cell niche. This niche collapse triggers a pathological competitive response from the epithelium, which undergoes aberrant bronchiolization that phenocopies human pulmonary fibrosis. Mechanistically, we uncovered a molecular switch that controls mesenchymal fate. During development and fibrosis resolution, Snail1/2 sequesters Yap/Taz to drive an adipogenic program, generating niche-supportive AF1s. Conversely, Yap/Taz-TEAD-Myc binding instructs a myogenic, pro-fibrotic program. Our findings demonstrate that inter-tissue cell competition, governed by a Snail/Yap rheostat, orchestrates lung architecture and provides a framework for targeting the mesenchymal niche to treat fibrotic disease.
    DOI:  https://doi.org/10.1038/s41467-025-66690-z
  24. bioRxiv. 2025 Oct 03. pii: 2025.10.03.680289. [Epub ahead of print]
    Progressive Loss of Astrocytic AIBP Expression during Alzheimer's Disease Pathology.
    Shihui Ding, Soo-Ho Choi, Yi Sak Kim, Nicolaus Nazarenkov, Yury I Miller.
      Astrocytes and microglia play crucial roles in mediating neuroinflammation during Alzheimer's disease (AD) progression. ApoA-I binding protein (APOA1BP, also known as AIBP/NAXE) attenuates neuroinflammation by blocking amyloid β-induced TLR4 inflammaraft formation and oxidative stress. Apoa1bp knockout in APP/PS1 mice exacerbates microgliosis, increases amyloid plaque burden, neuronal cell loss, and reduces survival at 6 months. Although APOA1BP mRNA is ubiquitously expressed in humans, its cell-type-specific distribution in the brain remains unclear. To examine AIBP protein expression in the human brain, we performed immunohistochemistry on hippocampal sections from postmortem brain specimens from subjects aged 75-96 of both sexes. Using GFAP and IBA1 to label astrocytes and microglia, respectively, we found that AIBP protein was highly expressed in astrocytes, but not in microglia. Stratification of subjects by Braak stage (I-II, III-IV, V-VI) revealed a progressive decline in astrocytic AIBP expression with advancing AD pathology. Meta-analysis of RNA-seq profiling indicated enriched Apoa1bp expression in adult mouse astrocytes. Systemic Apoa1bp knockout in the APP/PS1 mouse exacerbated astrogliosis. These findings demonstrate that AIBP is predominantly expressed in astrocytes and its expression declines with AD progression, suggesting a potential role for AIBP in astrocyte-mediated neuroprotection and AD pathogenesis.
    DOI:  https://doi.org/10.1101/2025.10.03.680289
  25. EMBO J. 2025 Nov 17.
    Microglial colonization of the developing mouse brain is controlled by both microglial and neural CSF-1.
    Cécile Bridlance, Sarah Viguier, Nicolas Olivié, Edmond Dupont, Dorine Thobois, Benjamin Mathieu, Jean X Jiang, Guillermina López-Bendito, Melanie Greter, Burkhard Becher, Florent Ginhoux, Aymeric Silvin, Esther Klinger, Sonia Garel, Morgane Sonia Thion.
      Microglia are brain-resident macrophages critical for cerebral development, function, and homeostasis. During development, yolk sac-derived microglial progenitor cells colonize and populate the brain following a well-defined spatiotemporal pattern. However, the mechanisms controlling microglial colonization and proliferation remain largely unknown. Here, we describe two broad waves of microglial proliferation in the developing mouse forebrain. Microglia accumulate in transient hotspots, in a proliferative axon tract-associated microglia (ATM)-like state. Prenatal and early postnatal patterns of microglial colonization do not rely on neuronal activity. Instead, using conditional inactivation of the microglial regulator colony-stimulating factor 1 (Csf1) gene, we reveal that the distribution and proliferation of embryonic cortical microglia critically rely on neural CSF-1, mainly produced by cortical progenitor cells but also by post-mitotic neurons, with the action of CSF-1 being local, dose-dependent, and transient. In addition, intrinsic CSF-1 expressed by ATM microglia contributes to their sustained proliferation in developmental hotspots. Our study reveals that microglia rely on distinct, local, and cell-type-specific sources of CSF-1 for their developmental distribution, which has major implications for understanding how microglia colonize the brain in health and disease.
    Keywords:  Colonization; Cytokine; Development; Microglia; Proliferation
    DOI:  https://doi.org/10.1038/s44318-025-00625-8
  26. Neuron. 2025 Nov 18. pii: S0896-6273(25)00803-7. [Epub ahead of print]
    C5aR1+ microglia exacerbate neuroinflammation and cerebral edema in acute brain injury.
    Jinpeng Zhou, Shuoyao Ma, Dayun Feng, Yang Tian, Leiyang Li, Hao Guo, Yingwu Shi, Wenxing Cui, Jingyu Dong, Sijia Hao, Chengxuan Guo, Meng Xu, Liying Han, Hao Bai, Dan He, Xiao Cui, Lian Chen, Xun Wu, Fei Gao, Qing Hu, Ziwen Zhang, Kai Wang, Gaoyang Zhou, Tian Feng, Dongzhi Xue, Qian Lin, Liang Wang, Li Gao, Lijun Heng, Tianzhi Zhao, Tao Luo, Bo Tian, Xingye Zhang, Wei Guo, Zhihong Li, Haixiao Liu, Shunnan Ge, Qiang Liu, Yan Qu.
      Microglia rapidly respond to acute brain injury and contribute to neuroinflammation that drives cerebral edema, a major cause of mortality and disability in stroke and traumatic brain injury (TBI). However, microglial heterogeneity complicates precise therapeutic targeting because specific disease-associated subtypes remain poorly characterized. Here, we define a previously unrecognized C5a receptor 1 (C5aR1)-expressing microglial subtype enriched in human cerebral edema tissue from decompressive surgery for TBI and intracerebral hemorrhage (ICH). In preclinical models, C5aR1+ microglia engage locally and peripherally derive C5a to amplify neuroinflammation, drive neurotoxic astrocyte polarization, and recruit neutrophils, leading to cerebral edema. Genetic ablation of microglial C5ar1 or its pharmacological inhibition with an Food and Drug Administration (FDA)-approved antagonist attenuates cerebral edema in both TBI and ICH. These findings delineate the role of C5aR1+ microglia in neuroinflammatory cascades and cerebral edema following acute brain injury, indicating C5aR1 as a potential therapeutic target.
    Keywords:  C5aR1(+) microglia; cerebral edema; microglial heterogeneity; neurotoxic astrocytes; neutrophils recruitment
    DOI:  https://doi.org/10.1016/j.neuron.2025.10.022
  27. Glia. 2026 Jan;74(1): e70101
    Microglial VRK2 Regulates Astrocytic GABA Synthesis and Tonic Inhibition in the Thalamus.
    Dongsu Lee, Go Eun Ha, Yeleen Lee, Denise Lee, Jongseo Lee, Jae Ho Yoon, Leechung Chang, Kyung Won Jo, Ho-Keun Kwon, Kyong-Tai Kim, Eunji Cheong.
      Vaccinia-related kinase 2 (VRK2) is a prominent genetic risk factor for neurodevelopmental disorders (NDDs), including schizophrenia and epilepsy, which are characterized by cognitive and behavioral impairments. The mediodorsal (MD) thalamus, a higher-order nucleus involved in executive function and social behavior, is frequently disrupted in these conditions. However, how VRK2 influences thalamic regulation remains unclear. Here, we show that Vrk2-deficient mice exhibit a significant reduction in tonic GABA currents in the MD thalamus, accompanied by decreased excitatory synaptic input but preserved intrinsic neuronal excitability. Although VRK2 is not expressed in astrocytes, its deletion impaired astrocyte-mediated tonic inhibition, suggesting a non-cell-autonomous mechanism. Single-cell and bulk transcriptomic analyses revealed that VRK2 is specifically expressed in microglia and that its loss alters cytokine signaling pathways. Pharmacological depletion of microglia or TNF-α inhibition in wild-type mice recapitulated the tonic inhibition deficits observed in Vrk2-deficient animals. Further, astrocyte-specific interventions revealed that tonic GABA is synthesized through the DAO-ALDH1A1 pathway, which was selectively downregulated in the absence of VRK2, while MAOB, BEST1, and GABA receptor components remained unchanged. These findings define a novel glial-glial signaling axis in which microglial VRK2 maintains thalamic inhibitory tone through cytokine-dependent regulation of astrocytic GABA synthesis. This mechanism operates across both first- and higher-order thalamic nuclei and may underlie sensory and cognitive impairments associated with VRK2-linked NDDs. Our work provides new insight into glial coordination as a critical regulator of tonic inhibition and highlights microglial cytokine signaling as a molecular bridge between genetic risk and circuit-level dysfunction.
    Keywords:  microglia; microglia‐astrocyte signaling; neurodevelopment disorder; thalamus; tonic GABA synthesis; tonic inhibition; vaccinia‐related kinase 2
    DOI:  https://doi.org/10.1002/glia.70101
  28. ArXiv. 2025 Sep 29. pii: arXiv:2509.25417v1. [Epub ahead of print]
    Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-seq Data.
    Sean Cottrell, Seungmin Yoon, Xiaoqi Wei, Alex Dickson, Guo-Wei Wei.
      Single-cell and single-nucleus RNA sequencing (scRNA-seq /snRNA-seq) are widely used to reveal heterogeneity in cells, showing a growing potential for precision and personalized medicine. Nonetheless, sustainable drug discovery must be based on a population-level understanding of molecular mechanisms, which calls for the population-scale analysis of scRNA-seq/snRNA-seq data. This work introduces a sequential target-drug selection model for drug repurposing against Alzheimer's Disease (AD) targets inferred from population-level snRNA-seq studies of AD progression in microglia cells as well as different cell types taken from an AD affected brain vascular tissue atlas, involving hundreds of thousands of nuclei from multi-patient and multi-regional studies. We utilize Persistent Sheaf Laplacians (PSL) to facilitate a Protein-Protein Interaction (PPI) analysis of AD targets inferred from differential gene expression (DEG), and then use machine learning models to predict repurpose-able DrugBank compounds for molecular targeting. We screen the efficacy of different DrugBank small compounds and further examine their central nervous system (CNS)-relevant ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity), resulting in a list of lead candidates for AD treatment. The list of significant genes establishes a target domain for effective machine learning based AD drug repurposing analysis of DrugBank small compounds to treat AD related molecular targets.
  29. Nat Commun. 2025 Nov 18. 16(1): 10098
    Plexin-B1 safeguards astrocyte agility and glial alignment to facilitate wound corralling and axon pathfinding in mouse spinal cord injury model.
    Haofei Ni, Zhilai Zhou, Molly Estill, Dalia Halawani, Chrystian Junqueira Alves, Li Shen, Ning Xie, Roland H Friedel, Hongyan Zou.
      Glial spatial organization is critical for neural repair after spinal cord injury (SCI). In response to injury, reactive astrocytes extend hypertrophic processes to corral the lesion core and sequester debris and inflammatory cells. How these long, arborized processes remain intact, and how astrocytes avoid collisions to assemble a glial bridge to guide axon pathfinding across lesion site remains unclear. Here we identify the guidance receptor Plexin‑B1 as a regulator of membrane integrity, process plasticity, and astrocyte alignment. Live‑cell imaging reveal that Plexin‑B1 deletion triggers membrane shedding and slows extension and retraction of astrocytic processes. The loss of astrocyte agility disrupts contact‑dependent avoidance, leading to disorganized astrocytes and misguided axons in vitro and in vivo. Mice with astrocyte‑specific Plexin‑B1 deletion show defective glial border, enlarged lesions, inflammatory spill‑over, and dysregulated astrocyte-microglia signaling. These defects result in impaired axon regeneration and poorer functional recovery after spinal‑cord injury. Thus, Plexin‑B1-mediated agility of astrocyte processes safeguards membrane integrity and spatial alignment, enabling effective wound corralling and axon pathfinding during neural repair following SCI.
    DOI:  https://doi.org/10.1038/s41467-025-65095-2
  30. Clin Transl Med. 2025 Nov;15(11): e70527
    Spatiotemporal mapping reveals Ccl8hi macrophages as key drivers of testicular inflammaging.
    Yanping Huang, Jiahui Yao, Zhiqiang Zhang, Bin Ouyang, Jintao Zhuang, Xianshen Sha, Canhui Qu, Chengqiang Mo, Mujun Lu, Nanhe Lin, Xiangzhou Sun, Qiyun Yang, Yun Xie.
       BACKGROUND: Testicular macrophages (TMs) are key regulators of testicular immune privilege and endocrine function in the testis. However, their age-related heterogeneity and role in testicular degeneration remain poorly characterized.
    METHODS: We performed spatial transcriptomics and FACS-enriched single-cell RNA sequencing (scRNA-seq) to characterize testicular macrophage heterogeneity across ageing. Key findings were validated through intratesticular injection of recombinant CCL8 protein, organotypic culture of seminiferous tubules, and immunofluorescence analysis.
    RESULTS: Using spatial transcriptomics, we identified pronounced Leydig niche senescence in aged testes, mechanistically linked to TM-mediated inflammatory remodelling. Coupling FACS-enriched TM isolation with scRNA-seq resolved seven transcriptionally distinct subpopulations, including ageing-associated subsets (Ccl8hi and Cxcl13hi). These subsets exhibited inflammatory signalling rewiring (e.g., CCL8-CCR2 axis) and activation of senescence transcriptional regulators (ASCL2, SPI1, CEBPB, JUNB), with conserved mediators (CCL8, TREM2, IL1β, and CXCL2) across murine and human testes. Functional validation showed that intratesticular injection of recombinant CCL8 protein in 3-month-old mice recapitulated ageing phenotypes, such as germ cell apoptosis and steroidogenic decline.
    CONCLUSIONS: Our multi-omics atlas highlights TM heterogeneity as a driver of testicular inflammaging and identifies CCL8 as a conserved target for therapeutic interventions aimed at mitigating age-associated male reproductive decline.
    KEY POINTS: Spatiotemporal multi‑omics establish inflammaging as a defining feature of testicular ageing. A refined CD74‑based sorting strategy improves enrichment of testicular macrophages. scRNA-seq resolves seven TM subsets with age‑dependent shifts. TM‑secreted inflammatory mediators-especially CCL8-drive testicular inflammaging.
    Keywords:  CCL8; inflammaging; spatiotemporal transcriptomics; testicular macrophages
    DOI:  https://doi.org/10.1002/ctm2.70527
  31. Life Sci Alliance. 2026 Feb;pii: e202503434. [Epub ahead of print]9(2):
    Müller cell glutamine metabolism links photoreceptor and endothelial injury in diabetic retinopathy.
    Katia Corano Scheri, Yi-Wen Hsieh, Thomas Tedeschi, James B Hurley, Amani A Fawzi.
      We characterized the timeline of molecular dysfunction in diabetic retinopathy (DR) and diabetic retinal disease (DRD) by studying the streptozotocin (STZ)-induced mouse retina over the course of 6 mo of diabetes. We performed bulk RNA-Seq on endothelial and retinal cells, separately, at 1, 3, and 6 mo of diabetes and single-cell RNA-Seq (scRNA-Seq) at 3 months. Transcriptomics changes were validated by in vitro and ex vivo assays and immunohistochemistry of mouse and human tissue. Bulk RNA-Seq revealed inflammation in endothelial cells at 1 mo. At 3 mo, scRNA-Seq identified glutamine-driven anaplerotic dysfunction in Müller cells, confirmed by retinal culture. We posited this glutamine deficiency would impact the photoreceptors and endothelial cells. We validated this hypothesis using endothelial cells in vitro, and immunohistochemistry of disrupted photoreceptor ribbon synapses in mouse and human diabetic retinas. In addition, glutamine deprivation increased the expression of apoptotic genes in endothelial cells. At 6 mo, we observed significant down-regulation of angiogenic pathways and elevated profibrotic markers. Our results suggest that dysfunction of the metabolic ecosystem linking the Müller-photoreceptor-endothelial cells is central to the early stages of DRD pathogenesis, impacting photoreceptor synapses and endothelial cells, before the appearance of the classic microvascular features of DR.
    DOI:  https://doi.org/10.26508/lsa.202503434
  32. Mol Brain. 2025 Nov 21. 18(1): 87
    Deficiency of SARM1 attenuates neuronal injury and improves neurological performance in a photothrombotic stroke model.
    Yanjie Huang, Xiaofeng Cheng, Ke Yan, Yufan Ma, Qingwu Yang, Sen Lin.
      Stroke is a major cause of morbidity and mortality worldwide. There is an urgent need for effective neuroprotective agents to reduce brain injury. SARM1 (sterile alpha and TIR motif-containing 1) has been identified as a key mediator of axonal degeneration. However, its role in stroke and the underlying mechanisms remain insufficiently understood. In the present study, a mouse model of stroke with focal infarction in the cortex was used to investigate the potential relation between SARM1 and post-stroke brain injury. We found that SARM1 expression increased in neurons of the peri-infarct cortex at an early stage after photothrombotic stroke induction (PTI) and was evenly distributed between excitatory and inhibitory neurons. Deficiency of SARM1 improved neurological performance, reduced the infarct volume and the inflammatory response including reactive gliosis and TNF-α level after PTI. Meanwhile, SARM1 deficiency promoted neuronal preservation in the peri-infarct cortex and mitigated axonal degeneration, possibly because of reduced NAD+ consumption of neurons in the peri-infarct cortex. Additionally, we found that SARM1 deficiency inhibited glial scar formation and decreased activated microglia. FK866 and DSRM-3716, two recently reported pharmacological inhibitors of SARM1, failed to alleviate brain injury in mice with stroke. Our findings demonstrate that SARM1 deficiency attenuates ischemic neuronal injury and improves neurological performance post PTI, suggesting that the SARM1 signaling pathway could serve as a potential therapeutic target for stroke in the future.
    Keywords:  Axonal degeneration; Neuron injury; Neuroprotection; SARM1; Stroke
    DOI:  https://doi.org/10.1186/s13041-025-01251-5
  33. Alzheimers Dement. 2025 Nov;21(11): e70927
    Apolipoprotein E and Alzheimer's disease pathology in a diverse autopsy study.
    Claudia K Suemoto, Regina Paradela, Renata E P Leite, Vitor R Paes, Carlos A Pasqualucci, Eduardo Ferriolli, Mayana Zatz, Gabriel do Nascimento Santos, Marvin Afonso Longo Salvador de Alexandria, Ana C Pereira, Juan Fortea, Michel Naslavsky, Lea T Grinberg.
       INTRODUCTION: Apolipoprotein E allele 4 (APOE ε4) is the main genetic risk factor for late-onset Alzheimer's disease (AD), but most evidence comes from White populations in high-income countries. We investigated APOE and AD pathology in an ethnically diverse Brazilian autopsy cohort.
    METHODS: This cross-sectional study used Biobank for Aging Studies (BAS) data. AD pathology was evaluated with Braak, Consortium to Establish a Registry for Alzheimer's Disease, and Thal criteria. APOE genotypes were obtained from blood or brain tissue. Regression models were adjusted for age, sex, race, and education; interaction with race was tested.
    RESULTS: Among 1391 participants (mean age 75.1 ± 12.4 years, 50% women, 64% White), APOE ε4showed a dose response with greater AD pathological burden and higher odds of AD diagnosis, while APOE ε2/X was protective. APOE ε4/ε4 did not show full penetrance across age groups. Associations were similar in White and Black individuals.
    DISCUSSION: APOE ε4was strongly associated with AD pathology, with consistent associations across racial groups.
    HIGHLIGHTS: APOE ε4 increased AD neuropathological burden in Brazilians. APOE ε2/εX was protective against AD pathology. APOE ε4/ε4did not show full penetrance across age groups. Associations between APOE and AD pathology were similar by race. Large multiethnic autopsy study expands evidence beyond high-income country studies.
    Keywords:  Alzheimer's disease; apolipoprotein; genetics; race; risk factors
    DOI:  https://doi.org/10.1002/alz.70927
  34. Mol Neurobiol. 2025 Nov 21. 63(1): 126
    Proteome Signature of Alzheimer-Like Phenotypes in Frontal Cortices From Young and Old Individuals With Down Syndrome.
    Fabio Di Domenico, Viviana Greco, Antonella Tramutola, Monika Rataj-Baniowska, Eugenio Barone, Chiara Lanzillotta, Luisa Pieroni, D Allan Butterfield, Yann Herault, Sara Pagnotta, Tommaso Cassano, Elizabeth Head, Andrea Urbani, Marzia Perluigi.
      Down syndrome (DS) stands out as the most prevalent genetic contributor to intellectual disability, marked by the presence of an extra copy of chromosome 21 (HSA21). Notably, individuals with DS exhibit significant neuropathological changes for a diagnosis of Alzheimer's disease (AD), typically by the age of 50 years. To search for and identify biomarkers crucial for detecting and understanding the mechanisms involved in DS neuropathology, we conducted a protein expression analysis of post-mortem brain samples. We evaluated the frontal cortex of post-mortem brain samples from patients with DS both before and after the onset of AD pathology (DSAD), in comparison with age-matched healthy patients (CTRY and CTRO). Employing a comprehensive label-free shotgun proteomics approach, we sought to gain a deeper understanding of the intricate protein profiles associated with DS and its progression into DSAD. Collected results have been analyzed using specific databases and bioinformatics analysis software to understand relevant pathways, networks, and functions related to the experimental data. Our data support a genotype effect in DS at young and old ages that promotes specific proteome signatures associated with AD development. Notably, the affected signalling pathways encompass energy-related processes, synaptic transmission, and stress response. With aging, the dynamic shift in protein expression contributes to accelerating the neurodegenerative process, culminating in the manifestation of the AD phenotype.
    Keywords:  Alzheimer’s disease; Mass spectrometry; Mouse model; Proteome; Trisomy 21; Ts66Yah
    DOI:  https://doi.org/10.1007/s12035-025-05432-0
  35. Exp Mol Med. 2025 Nov 17.
    Redirecting microglia phenotype via inhibition of NFAT1 ameliorates deficits in mouse model of synucleinopathies.
    Michiyo Iba, Yeon-Joo Lee, Somin Kwon, Liam Horan-Portelance, Katherine Chang, Minhyung Kim, Natalie Landeck, Robert A Rissman, Seung-Jae Lee, Sungyong You, Changyoun Kim.
      The abnormal deposition of α-synuclein (α-syn) and neuroinflammation are key features of synucleinopathies. We recently demonstrated that leucine-rich repeat kinase 2 (LRRK2) and nuclear factor of activated T cells 1 (NFAT1) modulate the neurotoxic inflammation in synucleinopathies mediated by microglia. Therefore, we hypothesized that targeting NFAT1 might ameliorate the microglial neurotoxicity in synucleinopathies. Here we utilized 11R-VIVIT, an NFAT1 inhibitory peptide, in in vivo, ex vivo and in vitro synucleinopathy models to evaluate the effects of NFAT1 inhibition to test this hypothesis. The microglia in synucleinopathy mouse models become excessively activated due to chronic disease conditions, thereby increasing the expressions of proinflammatory cytokines in these cells and decreasing the expressions of genes associated with microglial mobility and phagocytosis, strongly associated with neurodegeneration and pathogenic α-syn deposition. However, we observed that the inhibition of NFAT1 decreased the microglial neuroinflammation, thereby ameliorating neurodegeneration and α-syn neuropathology in vivo. Furthermore, the comprehensive in vivo transcriptomic analysis of the microglia revealed that the inhibition of NFAT1 restored their mobility and phagocytic abilities via upregulations of related genes. Our study proposes that the inhibition of NFAT1 redirects the excessively activated microglia to active healthy microglia, thereby reducing synucleinopathy neurotoxicity.
    DOI:  https://doi.org/10.1038/s12276-025-01564-4
  36. Nat Commun. 2025 Nov 18. 16(1): 10109
    Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice.
    Zhongxin Han, Siyi Xiong, Ke Zeng, Zilong Xiao, Liying Zhang, Yufen Zhang, Jiaying Guo, Wenqiang Peng, Yingchao Xie, Weiwei Liu, Xiao Yu.
      Precise regulation of type I interferon signaling is crucial for effective immune defense against infectious diseases. However, the molecular mechanisms governing this pathway are not fully understood. Here, we show a function for palmitoylation in enhancing anti-malarial immune responses. Our findings reveal that ZDHHC9 enhances the type I interferon signaling by palmitoylating TBK1 at cysteine 292. Following infection with Plasmodium yoelii N67, the delicate balance between palmitoylation and depalmitoylation of TBK1 is disrupted. Specifically, upregulation of APT2 promotes persistent depalmitoylation of TBK1 and triggers its selective autophagic degradation via K48-linked polyubiquitination at lysine 251/372 by E3 ligase TRIM27. This process acts as a recognition signal for the cargo receptor NDP52, resulting in inhibition of the type I interferon pathway. Notably, inhibition of APT2 using ML349 elevates type I interferon levels and improves survival rates against N67 infection. Here, we show that targeting APT2-mediated TBK1 depalmitoylation is a potential therapeutic strategy for malaria and may also be applicable to other diseases driven by dysregulated type I interferon signaling.
    DOI:  https://doi.org/10.1038/s41467-025-65081-8
  37. Mol Neurobiol. 2025 Nov 20. 63(1): 98
    The CSF Levels of Mitochondrial Phosphoenolpyruvate Carboxykinase 2 as a Novel Biomarker in Alzheimer's Disease.
    Nazlıcan İlhan, Erdi Şahin, Sümeyra Ildız, Bedia Samancı, Pelin Sordu, Merve Alaylıoğlu, Başar Bilgiç, Haşmet Ayhan Hanağası, İbrahim Hakan Gürvit, Erdinç Dursun, Duygu Gezen-Ak.
      Studies have shown that the expression patterns of neurons and glia can be altered by the Aβ fragments. We hypothesized that genes regulated by Aβ-affected transcription factors (TFs) are most impacted by amyloid pathology, leading to significant expression changes. To test this, we focused on three key TFs namely, Jun, Fos, and RELA, and identified 13 common genes they regulate. Given AD-related neurodegeneration disrupts essential cellular processes like mitochondrial function and glucose metabolism, we selected PCK2 as a biomarker candidate from these 13 common genes. The present study included core CSF biomarker validated 154 AD, 41 non-AD MCI patients, and 16 individuals with subjective cognitive impairment. We measured the PCK2 levels in CSF of the cases and controls with ELISA. The PCK2 levels were significantly lower in the CSF of AD cases compared to SCI or non-AD MCI cases. The PCK2 levels of A - individuals were significantly lower than that of A + individuals. Similarly, T - or (N) - individuals exhibit significantly lower levels of CSF PCK2 compared to their + counterparts. Each area under the curve for the ROC analysis of CSF pTau(181)/CSF PCK2 ratio in SCI vs. AD, non-AD MCI vs. AD, A - vs. A + , T - vs. T + and (N) - vs. (N) + were higher than 84%. The sensitivity and specificity of each analysis were at least 76% and 83%; respectively. A positive correlation was determined between CSF PCK2 and Aβ1-42 in AD. PCK2, along with other mitochondrial proteins, could be utilized as a mitochondrial biomarker for neurodegeneration, and PCK2 levels should be investigated in large cohorts for verification.
    Keywords:  Alzheimer’s disease; Biomarker; Cerebrospinal fluid; PCK2; Phosphoenolpyruvate carboxykinase 2
    DOI:  https://doi.org/10.1007/s12035-025-05461-9
  38. Cell Rep. 2025 Nov 14. pii: S2211-1247(25)01336-1. [Epub ahead of print]44(11): 116564
    In situ amplification of α-synuclein amyloid fibril reveals a distinct polymorph related to Parkinson's disease and dementia with Lewy body.
    Tianyi Cao, Qinyue Zhao, Yuxuan Yao, Kaien Liu, Youqi Tao, Shiran Lv, Feng Gao, Yong Shen, Chao Ma, Wenying Qiu, Cong Liu, WeiDong Le, Dan Li.
      High-resolution structure determination of ex vivo amyloid fibrils offers critical mechanistic insights into amyloid polymorphism and heterogeneity of neurodegenerative diseases. However, purifying amyloid fibrils from diseased brains may favor certain polymorphs over others. Here, instead of purifying fibrils, we used in situ amplification (ISA) of α-synuclein (α-syn) fibrils in brain homogenates. Cryoelectron microscopy (cryo-EM) structural analysis of the ISA fibrils from patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) reveal polymorphic fibril ensembles of each case including fibrils with morphologies similar to previously reported Lewy fold, as well as many others. Remarkably, we determine the high-resolution structure of a distinct polymorph (ISA-P1) that differs from the Lewy fold but is similar to those of multiple system atrophy (MSA) and juvenile-onset synucleinopathy (JOS). Our work supports the existence of alternative α-syn fibril polymorphs in PD and DLB, some of which may share common prototypical folds across various synucleinopathies.
    Keywords:  CP: Neuroscience; amyloid fibril; in situ amplification; neurodegenerative disease; pathological heterogeneity; structural polymorphism
    DOI:  https://doi.org/10.1016/j.celrep.2025.116564
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