bims-micgli 2025-10-19 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–10–19
24 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.
Ablation of progranulin augments microglial activation and accelerates prion progression.
Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles.
Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways.
Microglial NLRP3 inflammasome activation leads to perineuronal net loss in cocultured neurons.
TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.
Alzheimer's alphabet soup: Find the letters "Z-DNA-ZBP1-RIPK1".
Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study.
Lipid-Metabolically Active TREM2high Microglia‑Derived Macrophages Predict Poor Prognosis and Represent an Immunotherapeutic Target in Glioma.
Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia.
Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency.
Central Zika virus infection causes hypothalamic inflammation and persistent insulin resistance in adult mice.
Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease.
Increase of brain Aβ peptides and secretase activity during normal aging in rodent and human.
Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.
Nanoparticle-boosted myeloid-derived suppressor cell therapy for immune reprogramming in multiple sclerosis.
Increased nucleotide metabolism alleviates Alzheimer's disease pathology.
Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer's Disease.
Homeostatic synaptic plasticity of miniature excitatory postsynaptic currents in mouse cortical cultures requires neuronal Rab3a.
Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling.
Cerebrospinal fluid proteomic signatures in cognitively normal individuals identify distinct clusters linked to neurodegeneration.
Lung tissue-resident memory T cells optimize protection by IL-10 regulation of innate immunity.
Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding.
Is TREM2 a Stretch: Implications of TREM2 Along Spinal Cord Circuits in Health, Aging, Injury, and Disease.

Nat Commun. 2025 Oct 15. 16(1): 9156

Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.

Ziying Xu, Sepideh Kiani Shabestari, Savannah Barannikov, Kevin F Bieniek, Mathew Blurton-Jones, Juan Pablo Palavicini, Xianlin Han.

Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a striking buildup of arachidonic acid-containing bis(monoacylglycero)phosphate in response to amyloid plaques, which depends on microglial activity and the AD risk gene GRN. In contrast, lysophosphatidylcholine and lysophosphatidylethanolamine accumulate independently of microglia, correlating instead with astrocyte activation and oxidative stress. These results connect dysregulated lipid metabolism in AD to distinct brain cell types and molecular pathways. Our findings highlight microglial lipid homeostasis as a potential therapeutic target for modifying disease progression in AD.

DOI: https://doi.org/10.1038/s41467-025-64161-z
Acta Neuropathol Commun. 2025 Oct 13. 13(1): 214

Ablation of progranulin augments microglial activation and accelerates prion progression.

Bei Li, Yiyue Shi, Wenyu Hou, Haoyuan Guan, Jun Li, Tuo Yi, Wei Li, Donglin Cai, Petra Schwarz, Adriano Aguzzi, Caihong Zhu.

  Mutations or polymorphisms in GRN, encoding the CNS glycoprotein progranulin (PGRN), have been linked to several neurodegenerative diseases. In this study, we explored the role of PGRN in prion diseases. We observed that prion infection upregulated microglial PGRN expression. Following intracerebral inoculation with RML6 prions, Grn-/- mice exhibited accelerated disease progression compared to Grn+/- and Grn+/+ littermates. Histological analysis revealed augmented microglial activation in Grn-/- mice. Temporal analysis revealed enhanced early microglial activation and prion clearance at 120 dpi, followed by excessive complement activation but inadequate clearance by 150 dpi. Additionally, Grn-/- brains exhibited exacerbated astrogliosis and vacuolation. RNA-seq analysis indicated that complete PGRN deficiency in prion-infected mice shifted microglia from homeostatic to pro-inflammatory states. Notably, microglia-specific depletion of PGRN did not affect prion pathogenesis, suggesting that PGRN deficiency affects microglial activation and prion progression in a non-cell autonomous manner. These findings suggest that microglia respond to prion infection in a stepwise manner, and PGRN plays a critical role in modulating prion-induced microglial activation. Our results highlight the neuroprotective role of PGRN in prion disease and suggest that supplementation or boosting expression of PGRN could represent a promising therapeutic strategy.

Keywords:  Microglia; Neurodegeneration; Neuroinflammation; Prion disease; Progranulin

DOI:  https://doi.org/10.1186/s40478-025-02128-3
Sci Transl Med. 2025 Oct 15. 17(820): eadq3401

Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles.

Yuichiro Itoh, Noriko Itoh, Sophia Wendin, Nadya Higgins, Rhonda R Voskuhl.

Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. Kdm6a is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of Kdm6a in microglia in MS because this cell type plays a key role in the neuropathology of MS. Kdm6a was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of Kdm6a in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of Kdm6a in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A's histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of KDM6A in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that KDM6A might contribute to sex differences in susceptibility to MS.

DOI: https://doi.org/10.1126/scitranslmed.adq3401
Mol Neurodegener. 2025 Oct 13. 20(1): 107

Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer's disease genetic pathways.

Bjørn-Eivind Kirsebom, Johanna Nilsson, Ellen Vromen, Peter Mikael Arnesen, Atle Bjørnerud, Ann Brinkmalm, Geir Bråthen, Gøril Rolfseng Grøntvedt, Jonas Jarholm, Kaja Nordengen, Lene Pålhaugen, Per Selnes, Nikias Siafarikas, Ragnhild Eide Skogseth, Sandra Tecelão, Knut Waterloo, Panpan You, Henrik Zetterberg, Dag Aarsland, Betty Tijms, Pieter Jelle Visser, Kaj Blennow, Tormod Fladby.

   BACKGROUND: Synapse loss is linked to cognitive symptoms in Alzheimer's Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets.
METHODS: We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins.
RESULTS: In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts.
CONCLUSIONS: Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.

Keywords:  Alzheimer’s disease; Cognition; Memory; Neurodegeneration; Synaptic loss

DOI:  https://doi.org/10.1186/s13024-025-00899-w
Mol Biol Rep. 2025 Oct 13. 52(1): 1023

Microglial NLRP3 inflammasome activation leads to perineuronal net loss in cocultured neurons.

Emre Tarakcioglu, Kemal Ugur Tufekci, Sermin Genc.

   BACKGROUND: Microglia play a crucial role in maintaining the health of the central nervous system (CNS) through synaptic pruning, debris clearance, and pathogen elimination; however, sustained microglial inflammation can lead to neuronal damage. The NLRP3 inflammasome, a key regulator of inflammatory responses, has been implicated in various CNS diseases. Perineuronal nets (PNNs) are specialized structures that encase neuron somas, protect neurons from oxidative stress, and stabilize synaptic connections. While inflammatory microglia can degrade PNNs, the specific role of inflammasomes in this degradation process remains unclear.
METHODS AND RESULTS: To investigate the role of inflammasomes in degradation of PNNs, neurons were derived from the murine Neuro-2a cell line using retinoic acid. Subsequently, we induced the NLRP3 inflammasome in the murine N9 microglial cell line via exposure to lipopolysaccharide and ATP. The effect of NLRP3 activation on degradation of PNNs was examined by coculturing neurons and microglia with and without NLRP3 inhibition for 24 h. PNNs were quantified using immunofluorescence staining with Wisteria floribunda agglutinin and neurocan antibodies, both of which bind to PNNs. Our findings demonstrate that coculture with NLRP3-activated microglia reduces the percentage of WFA- and neurocan-positive neurons whereas the inhibition of NLRP3 reverses this effect.
CONCLUSIONS: Our findings highlight the significant role of the NLRP3 inflammasome in the degradation of PNNs in inflammatory states. Moreover, our research suggests that targeting the NLRP3 inflammasome could protect PNN-positive neurons from the damaging effects of inflammation. These findings might provide insight into the inflammatory mechanisms underlying loss of PNNs.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  Inflammation; Microglia; Neuroinflammation; Neuron; Perineuronal net

DOI:  https://doi.org/10.1007/s11033-025-11145-3
Alzheimers Dement. 2025 Oct;21(10): e70729

TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.

Rory A Greer, Ryan A Tuckey, Hunter B Dean, Thomas J Brett, Erik D Roberson, Yuhua Song.

   INTRODUCTION: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2-apoE3 interactions and effects of AD-associated variants on TREM2-apoE3 interactions are not fully understood.
METHODS: We used consensus protein-protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2-apoE3 complex structure and examine AD-associated TREM2 R47H, and apoE4 variants effects.
RESULTS: Our experimentally consistent TREM2-apoE3 complex structure identified new potential TREM2-apoE3 interactions alongside the known interactions. TREM2-apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD-associated TREM2 R47H and apoE4 variants altered TREM2-apoE binding mode and conformational stability.
DISCUSSION: This study determined an experimentally consistent TREM2-apoE3 complex structure and revealed a potential mechanism that AD-associated TREM2 R47H variant alters TREM2-apoE3 binding mode. Understanding TREM2-apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD-associated variants.
HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are two strong genetic risk factors for Alzheimer's disease (AD). An experimentally consistent TREM2-apoE3 complex structure was determined. New potential interaction interfaces between TREM2 and apoE3 were identified. TREM2-apoE3 interactions altered TREM2 and apoE3 conformation. AD-associated TREM2  R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2-apoE complexes.

Keywords:  AD‐associated TREM2 R47H variant; TREM2‐apoE3 complex structure; alzheimer's disease; apolipoprotein E4; binding free energy analyses; experimentally guided consensus protein–protein docking; molecular dynamics simulations; triggering receptor expressed on myeloid cells 2

DOI:  https://doi.org/10.1002/alz.70729
Immunity. 2025 Oct 14. pii: S1074-7613(25)00421-2. [Epub ahead of print]58(10): 2367-2369

Alzheimer's alphabet soup: Find the letters "Z-DNA-ZBP1-RIPK1".

Jake A Gertie, Hachung Chung.

Neuroinflammation contributes to Alzheimer's disease (AD), but the molecules and pathways that initiate inflammation are unclear. In this issue of Immunity, Song et al. demonstrate that ZBP1-RIPK1 signaling in microglia can drive AD, wherein ZBP1 is activated by left-handed Z-DNA leaking from mitochondria, presenting new molecular targets for AD therapeutics.

DOI: https://doi.org/10.1016/j.immuni.2025.09.010
Mol Neurodegener. 2025 Oct 17. 20(1): 109

Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study.

Mariana I Muñoz-García, Yuetiva Deming, Ferran Lugo-Hernández, Sterling Johnson, Sanjay Asthana, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Cynthia Carlsson, Ozioma C Okonkwo, David Pérez-Martinez, Alberto Villarejo-Galende, Kaj Blennow, Marc Suárez-Calvet, Henrik Zetterberg, Barbara B Bendlin, Estrella Morenas-Rodríguez.

   BACKGROUND: Synaptic homeostasis, maintained by microglia and astroglia, is disrupted throughout aging and early on in neurodegenerative diseases. Our aim was to study the relationship between TREM2-dependent microglial reactivity, astroglial response and synaptic dysfunction in two longitudinal cohorts of cognitively healthy volunteers and determine whether this relationship is influenced by AD core biomarkers.
METHODS: We analyzed cross-sectional and longitudinal associations between cerebrospinal fluid levels of soluble TREM2 (sTREM2), astroglial markers (GFAP, S100B), and synaptic markers (neurogranin, α-synuclein) in cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) and the Alzheimer's and Families (ALFA+) cohort. Biomarkers were quantified using validated immunoassays (NeuroToolKit, Roche), with sTREM2 measured using an in-house MSD-based assay in the WRAP cohort. Linear regression and linear mixed-effects models were used, both unadjusted and adjusted for Aβ42 and p-tau. Subgroup analyses were performed based on AT classification, APOE-ε4 status, and median splits of Aβ42/Aβ40 ratio and p-tau, to capture profiles suggestive of early AD-related neuropathogenesis.
RESULTS: We found significant cross-sectional associations between sTREM2 and α-synuclein, as well as between sTREM2 and S100B, in subgroups exhibiting AD-related biomarker profiles. Longitudinally, lower baseline neurogranin and α-synuclein and higher S100B predicted greater increases in sTREM2 over time independently of AD-related markers in the WRAP cohort (β = -0.02, p = 0.006; β = -0.02, p = 0.01; β = 0.02, p = 0.03, respectively). In ALFA+, lower baseline α-synuclein also predicted a greater subsequent longitudinal increase in sTREM2, but only among individuals with Aβ42/Aβ40 ratio above the median (β = -0.01, p = 0.05). Notably, higher baseline sTREM2 was associated with a smaller longitudinal increase in neurogranin in both cohorts (β = -0.01, p = 0.03 for WRAP, β = -0.01, p = 0.04 in ALFA+).
CONCLUSIONS: Synaptic dysfunction markers at baseline influence the longitudinal dynamics of CSF sTREM2 independently of AD-pathology related biomarkers throughout aging and earliest stages of neurodegeneration. In turn, higher baseline sTREM2 is associated with more stable neurogranin levels over time. These results suggest an independent interaction between synaptic dysfunction and TREM2-dependent microglial activation throughout aging and early neurodegeneration beyond AD pathology.

Keywords:  Aging; Microglia; Neurodegeneration; Synaptic function; TREM2

DOI:  https://doi.org/10.1186/s13024-025-00901-5
J Neuroimmune Pharmacol. 2025 Oct 14. 20(1): 92

Lipid-Metabolically Active TREM2high Microglia‑Derived Macrophages Predict Poor Prognosis and Represent an Immunotherapeutic Target in Glioma.

Jinxin Li, Xiaotong Yu, Decao Yang, Shaomeng Chen, Jiaxing Xu, Xiaojuan Ma, Chen Huang, Baohui Xu, Lixiang Xue, Yan Wang.

  Gliomas are the most common primary brain tumors and characterized by poor prognosis and heavy infiltration of tumor-associated macrophages. Triggering receptor expressed on myeloid cells-2 (TREM2), known to modulate macrophage function, has shown conflicting roles in glioma pathology. In this study, we comprehensively investigated the expression, function, and clinical relevance of TREM2 in gliomas using public datasets, single-cell RNA sequencing (scRNA-seq) analysis, and multiplex immunofluorescence. scRNA-seq identified a distinct subset of microglia-derived macrophages with high TREM2 expression that exhibit a dual phenotype of immunosuppression and enhanced lipid metabolism. These cells show enrichment of genes involved in fatty acid metabolism and lipoprotein clearance, including significant upregulation of apolipoprotein E (APOE), a known TREM2 ligand. Clinically, high TREM2 expression in microglia-derived macrophages correlates with increased tumor grade, recurrence, and shorter overall and disease-free survival. In contrast, APOE expression was correlated with better survival in public datasets, though not significantly in our patient cohort. Our findings suggest that TREM2high microglia-derived macrophages constitute a pro-tumorigenic subpopulation within the glioma microenvironment and may serve as a robust prognostic marker. The interplay between TREM2 and APOE further underscores the immunometabolic complexity of gliomas and points to TREM2 as a promising target for therapeutic intervention.

Keywords:  APOE; Glioma; Macrophage; Microglia; TREM2

DOI:  https://doi.org/10.1007/s11481-025-10250-1
Nat Commun. 2025 Oct 14. 16(1): 9123

Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia.

Alyssa M Wilson, Michelle M Jacobs, Tova Y Lambert, Aditi Valada, Gregory Meloni, Evan Gilmore, Jacinta Murray, Susan Morgello, Schahram Akbarian.

For people with HIV, substance use disorders are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways may pose a deleterious convergence. Here, we profile, at single nucleus resolution, substantia nigra transcriptomes of 90 postmortem donors in the context of chronic HIV and opioid/cocaine use disorders, including 67 prospectively characterized people with HIV. We report altered microglial expression for hundreds of pro- and anti-inflammatory regulators attributable to HIV, and separately, to opioid/cocaine disorders. Stepwise, progressive microglial dysregulation coupled to altered dopaminergic/GABAergic signaling is associated with substance/HIV dual diagnosis, and further with lack of viral suppression in blood. In suppressed donors, opioid/cocaine comorbidity is associated with microglial transcriptional changes permissive for HIV infection. Finally, HIV-related downregulation of monoamine reuptake transporters emerges specifically in dopaminergic neurons regardless of substance use disorder status or viral load, as do transcriptional signatures consistent with selective vulnerability of dopamine neurons.

DOI: https://doi.org/10.1038/s41467-025-64193-5
Nat Commun. 2025 Oct 17. 16(1): 9240

Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency.

Alysa Kasen, Sofia Lövestam, Libby Breton, Lindsay Meyerdirk, Jacob Alec McPhail, Kristin Piche, Ariel Louwrier, Colt D Capan, Hyoungjoo Lee, Sjors H W Scheres, Michael X Henderson.

Tau misfolding into β-sheet-rich filaments and subsequent recruitment of monomeric tau are central to Alzheimer's disease (AD) pathogenesis. While cryo-EM has resolved the conformation of the AD tau core, the structural features conferring biological activity remain unclear. Here, we investigated how tau filament core structure and post-translational modifications influence seeding capacity in neurons and mice. Our findings show that although filament structure impacts seeding, the AD tau core alone is insufficient to fully replicate AD tau's biological activity. The unstructured fuzzy coat, particularly phosphorylation within this region, is essential for full seeding competence. Importantly, recombinant tau filaments bearing twelve phospho-mimetic residues (PAD12 tau) and adopting the AD fold recapitulate the seeding activity of native AD tau. These results demonstrate that tau filament pathogenicity arises from the combined contributions of both the ordered core structure and post-translational modifications within the fuzzy coat, providing critical insights into mechanisms underlying tau-driven neurodegeneration.

DOI: https://doi.org/10.1038/s41467-025-64312-2
Cell Death Dis. 2025 Oct 13. 16(1): 722

Central Zika virus infection causes hypothalamic inflammation and persistent insulin resistance in adult mice.

Emanuelle V de Lima, Clara O Nogueira, Raissa R Christoff, Emylle Costa-Bartuli, Tathiany Igreja-Silva, Mariana Oliveira Lopes da Silva, Daniel Gavino-Leopoldino, Maria Luiza Móra Santos, Felipe Simões Lemos, Jaderson C da Costa, Gianina T Venturin, Iranaia Assunção-Miranda, João M N Duarte, Claudia P Figueiredo, Giselle F Passos, Julia R Clarke.

Zika virus (ZIKV) is a neurotropic flavivirus capable of infecting the adult brain, however its impact on hypothalamic function and metabolic regulation remains unclear. Here, we show that ZIKV invades the hypothalamus of immunocompetent adult mice, where it replicates and persists, leading to sustained insulin resistance. Following infection, ZIKV RNA and negative strand were detected in the hypothalamus of mice and immunostaining confirmed viral proteins in neurons, especially POMC-positive cells. At 6 dpi, ZIKV induced hypothalamic neuroinflammation, as shown by the upregulation of TNF-α, IL-6, IFN-β, and ISG-15, as well as microglial activation. These inflammatory responses were associated with impaired insulin signaling, characterized by reduced phosphorylation of IRS-1 and S6K, downregulation of insulin receptor mRNA, and decreased anorexigenic response following intracerebral insulin administration. Our data also showed that, despite viral clearance and resolution of hypothalamic inflammation at 30 dpi, reduction in insulin receptor protein levels and hypothalamic insulin resistance persisted. These findings demonstrate that ZIKV replicates in the hypothalamus of immunocompetent adult mice, leading to long-lasting disruption of central insulin signaling. Our study identifies hypothalamic insulin resistance as a novel consequence of ZIKV central nervous system invasion and suggests that viral infections may contribute to long-term metabolic dysfunction, highlighting the need to investigate persistent hypothalamic and metabolic alterations in ZIKV infection-recovered individuals.

DOI: https://doi.org/10.1038/s41419-025-08046-5
Alzheimers Dement. 2025 Oct;21(10): e70738

Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease.

Eleonora M Vromen, Senne B Lageman, Johan Gobom, Rik van der Kant, Valerija Dobricic, Lars Bertram, Johannes Streffer, Simon Lovestone, Stephanie J B Vos, Mikel Tainta, Yvonne Freund-Levi, Lutz Frölich, Julius Popp, Gwendoline Peyratout, Magda Tsolaki, Frans Verhey, Rik Vandenberghe, Jolien Schaeverbeke, Kaj Blennow, Sven J van der Lee, Philip Scheltens, Yolande A L Pijnenburg, Wiesje M van der Flier, Charlotte E Teunissen, Henrik Zetterberg, Pieter Jelle Visser, Betty Tijms.

   BACKGROUND: The apolipoprotein E (APOE) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied APOE genotype effects on the cerebrospinal fluid (CSF) proteome.
METHODS: Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A-T-), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across APOE genotypes using linear regression and characterized biological pathways.
RESULTS: Five hundred forty-nine of 978 proteins (56%) differed between ε2/ε3 (n = 32 individuals) or ε4 carriers (n = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood-brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.
DISCUSSION: Combining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.
HIGHLIGHTS: Apolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD). Combining cohorts enabled analysis of rare APOE ε2-associated protection in AD. The rare ε2 genotype may confer protection through improved neuronal plasticity. APOE ε4 carriers show increased blood-brain barrier dysfunction and glucose metabolism. These findings offer new insights into genotype-specific mechanisms in early AD.

Keywords:  Alzheimer's disease; apolipoprotein E; cerebrospinal fluid; cognitively normal; mild cognitive impairment; protection; proteomics; risk

DOI:  https://doi.org/10.1002/alz.70738
Geroscience. 2025 Oct 14.

Increase of brain Aβ peptides and secretase activity during normal aging in rodent and human.

Jose A Godoy-Lugo, Max A Thorwald, Elizabeth Head, Ashley L Gomm, Can Zhang, Rudolph E Tanzi, Caleb E Finch.

  Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration.

Keywords:  Aging; Aβ peptides; Secretase activity

DOI:  https://doi.org/10.1007/s11357-025-01926-w
ACS Chem Neurosci. 2025 Oct 16.

Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.

Athira Sasidharan, Yogish Somayaji, Ronald Fernandes.

  Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.

Keywords:  Alzheimer’s disease (AD); diseases associated with microglia (DAM); microglia; microglial neurodegenerative phenotype (MGnD); neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.1021/acschemneuro.5c00159
Sci Adv. 2025 Oct 17. 11(42): eady4135

Nanoparticle-boosted myeloid-derived suppressor cell therapy for immune reprogramming in multiple sclerosis.

Endong Zhang, Hanan Algarni, Luyu Zhang, Chih-Jia Chao, Shan He, Aditi Upadhye, Qing Bao, Dahee Jung, Shubhi Srivastava, Edidiong Udofa, Philana Phan, Dejan S Nikolic, Steve Seung-Young Lee, Jalees Rehman, Zongmin Zhao.

Massive immune cell infiltration and persistent inflammation in the central nervous system (CNS) are key hallmarks of multiple sclerosis. Here, we report a myeloid-derived suppressor cell (MDSC)-based therapeutic strategy, named CNS Immune Targeting Enabled by MDSCs (CITED), which uses surface-decorated MDSCs carrying rapamycin nanoparticles (NPs) for targeted multimodal immune reprogramming in CNS. We show that NP decoration enhances MDSC immunomodulatory function, facilitates their trafficking to inflamed CNS regions, and increases NP accumulation within CNS. In an experimental autoimmune encephalomyelitis model, CITED exhibited robust therapeutic efficacy, resulting in reduced disease progression, improved motor function, and diminished myelin damage. Mechanistic studies reveal that CITED exerts its therapeutic effects by targeted reprogramming of both innate and adaptive immune responses in CNS. Specifically, CITED inhibits immune cell infiltration, rebalances CD4 T cell phenotypes, and promotes the polarization of myeloid cells toward anti-inflammatory phenotypes. Collectively, CITED could provide a broadly effective approach for targeted immune restoration in multiple sclerosis and potentially other autoimmune diseases.

DOI: https://doi.org/10.1126/sciadv.ady4135
Cell Death Dis. 2025 Oct 16. 16(1): 724

Increased nucleotide metabolism alleviates Alzheimer's disease pathology.

Yizhou Yu, Michael B Miller, August Yue Huang, Bryan Wei Zhi Tan, Ivana Celardo, Nuno Santos Leal, Samantha H Y Loh, L Miguel Martins.

Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP‒ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is linked to a lower risk of developing AD. Our results suggest that enhancing nucleotide metabolism could improve DNA repair and serve as an adjunct therapy to delay AD progression.

DOI: https://doi.org/10.1038/s41419-025-08066-1
Mol Neurodegener. 2025 Oct 13. 20(1): 105

Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer's Disease.

Livia La Barbera, Paraskevi Krashia, Gilda Loffredo, Emma Cauzzi, Maria Luisa De Paolis, Martina Montanari, Luana Saba, Elena Spoleti, Serena Ficchì, Claudio Zaccone, Marco De Bardi, Claudia Palazzo, Ramona Marino, Emanuele Claudio Latagliata, Stefano Puglisi-Allegra, Giovanna Borsellino, Flavio Keller, Luisa Lo Iacono, Maria Teresa Viscomi, Annalisa Nobili, Marcello D'Amelio.

   BACKGROUND: Smaller midbrain volumes predict Alzheimer's Disease (AD) progression and faster conversion from Mild Cognitive Impairment (MCI) to dementia. Along with this, various midbrain-target areas are characterized by neuroinflammation since the MCI stage. The concomitance of neuroinflammation, Αβ and tau appears to be a strong predictor for conversion from MCI to dementia. Yet, how midbrain degeneration could cause disease progression, and what mechanisms are involved in triggering neuroinflammation in midbrain-target areas such as the hippocampus remain unexplored.
METHODS: Using adult C57BL/6N mice we generated a new mouse model carrying lesions in three midbrain nuclei, the dopaminergic Ventral Tegmental Area (VTA) and Substantia Nigra pars compacta (SNpc) and the serotonergic Interpeduncular Nucleus (IPN), to evaluate the consequences of dopamine and serotonin deprivation in midbrain-target areas. We characterized this model by performing stereological cell counts, analysis of monoaminergic fibers, monoamine levels, electrophysiology and behavioral tests. We then assessed hippocampal neuroinflammation by analyzing glia cell count, changes in morphology, NLRP3 inflammasome activation and cytokine levels, and microglia transcriptional profiling. In a separate set of experiments, we induced experimental midbrain lesion in Tg2576 transgenic mice overexpressing the Swedish mutant amyloid precursor protein, to evaluate the effect of monoamine deprivation on the hippocampus in concomitance with amyloid-β (Aβ) accumulation. The lesion performed in Tg2576 mice, as opposed to that in C57BL/6N mice, provides valuable insights into how neuroinflammation is influenced by Aβ accumulation versus the exclusive impact of impaired monoaminergic signaling.
RESULTS: The concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.
CONCLUSIONS: These results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance towards a precision medicine approach in disease management.

Keywords:  Cognitive decline; Gene expression profiling; Mesolimbic system; Monoamines; Neurodegenerative disease; SSRI; Synaptic plasticity; Transcriptome

DOI:  https://doi.org/10.1186/s13024-025-00893-2
Elife. 2025 Oct 14. pii: RP90261. [Epub ahead of print]12

Homeostatic synaptic plasticity of miniature excitatory postsynaptic currents in mouse cortical cultures requires neuronal Rab3a.

Andrew G Koesters, Mark M Rich, Kathrin Engisch.

  Following prolonged activity blockade, amplitudes of miniature excitatory postsynaptic currents (mEPSCs) increase, a form of plasticity termed 'homeostatic synaptic plasticity'. We previously showed that a presynaptic protein, the small GTPase Rab3a, is required for full expression of the increase in miniature endplate current amplitudes following prolonged blockade of action potential activity at the mouse neuromuscular junction (NMJ) in vivo, where an increase in postsynaptic receptors does not contribute. It is unknown whether this form of Rab3a-dependent homeostatic plasticity at the NMJ shares any characteristics with central synapses. We show here that homeostatic synaptic plasticity of mEPSCs is impaired in mouse cortical neuron cultures prepared from Rab3a-/- and mutant mice expressing a single-point mutation of Rab3a, Rab3a Earlybird mice. To determine if Rab3a is involved in the well-established homeostatic increase in postsynaptic AMPA-type receptors (AMPARs), we performed a series of experiments in which electrophysiological recordings of mEPSCs and confocal imaging of synaptic AMPAR immunofluorescence were assessed within the same cultures. We found that the increase in postsynaptic AMPAR levels in wild-type cultures was more variable than that of mEPSC amplitudes, which might be explained by a presynaptic contribution, but we cannot rule out variability in the measurement. Finally, we demonstrate that Rab3a is acting in neurons because only selective loss of Rab3a in neurons, not glia, disrupted the homeostatic increase in mEPSC amplitudes. This is the first demonstration that a protein thought to function presynaptically is required for homeostatic synaptic plasticity of quantal size in central neurons.

Keywords:  AMPA receptors; Rab3a; homeostatic synaptic plasticity; mEPSCs; mouse; neuroscience; synaptic scaling

DOI:  https://doi.org/10.7554/eLife.90261
Nat Commun. 2025 Oct 17. 16(1): 9220

Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling.

Klara Piletic, Amir H Kayvanjoo, Felix Clemens Richter, Mariana Borsa, Ana V Lechuga-Vieco, Oliver Popp, Sacha Grenet, Jacky Ka Long Ko, Lin Luo, Kristina Zec, Maria Kyriazi, Harriet K Haysom, Lada Koneva, Stephen Sansom, Philipp Mertins, Fiona Powrie, Ghada Alsaleh, Anna Katharina Simon.

A hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Using a mouse model, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy restrains purine nucleoside metabolism in obese adipocytes. This ultimately leads to a reduced release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings in mice reveal a role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases.

DOI: https://doi.org/10.1038/s41467-025-64266-5
Nat Aging. 2025 Oct;5(10): 2125-2141

Cerebrospinal fluid proteomic signatures in cognitively normal individuals identify distinct clusters linked to neurodegeneration.

Dahun Seo, Anh N Do, Gyujin Heo, Jiseon Kwon, Soomin Song, Catherine Apio, Cheolmin Matthew Lee, Jigyasha Timsina, Katherine Gong, Yike Chen, Menghan Liu, Pat Kohlfeld, John Budde, Merce Boada, Adelina Orellana, Maria Victoria Fernandez, Agustin Ruiz, John C Morris, Suzanne E Schindler, Laura Ibanez, Taesung Park, Carlos Cruchaga, Yun Ju Sung.

Age and APOE ε4 are major risk factors for Alzheimer's disease (AD), while sex differences exist in disease prevalence and progression. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and AD. To examine proteomic changes due to age, sex and apolipoprotein E (APOE) ε4 along with amyloid status before clinical AD occurs, we profiled 6,175 proteins in the CSF from 994 cognitively normal individuals aged 43-91 years. We identified and replicated 2,172 age-associated, 711 sex-associated, 193 APOE ε4-associated and 1,807 amyloid-associated proteins, with extensive overlap suggesting their interplay. These CSF-specific signatures were distinct from those in plasma. Network analysis revealed two proteomic modules-M2 (age-associated, sex-associated and amyloid-associated) and M6 (age-associated and sex-associated)-which were linked to neuropsychiatric and aging-related diseases. Together, our study provides proteomic changes during the early phase of AD, which may help identify new therapeutic targets of AD.

DOI: https://doi.org/10.1038/s43587-025-00971-6
J Exp Med. 2026 Jan 05. pii: e20242307. [Epub ahead of print]223(1):

Lung tissue-resident memory T cells optimize protection by IL-10 regulation of innate immunity.

Alexander Y Yang, Julia Davis-Porada, Daniel H Paik, Alex B George, Brea H Brown, Paige L Ruschke, Peter A Sims, Ziv Frankenstein, Anjali Saqi, Donna L Farber.

Respiratory viral infections establish tissue-resident memory T cells (TRM) in the lung, which provide optimal protection against subsequent infections, though the underlying mechanisms are incompletely understood. Here, we demonstrate in a mouse model of heterosubtypic influenza infection that lung TRM attenuate inflammation by macrophages during secondary versus primary responses, in part, through production of the immunoregulatory cytokine IL-10. During secondary infections, lung TRM were the predominant producers of early IL-10; inhibiting early IL-10 signaling resulted in increased macrophage-mediated inflammation, morbidity, and lung pathology. Moreover, lung TRM were shown to directly modulate lung macrophage responses and polarization in depletion experiments. Finally, IL-10 enhanced IFN-γ production by lung memory CD8+ T cells. Human influenza-specific TRM isolated from lungs recapitulated robust IL-10 expression associated with augmented effector responses of murine TRM. These data support a dual role of TRM in coordinating in situ secondary responses-augmenting effector responses for robust viral clearance while dampening inflammation to limit tissue damage.

DOI: https://doi.org/10.1084/jem.20242307
EMBO J. 2025 Oct 17.

Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding.

Francesca Simonetti, Weijia Zhong, Saskia Hutten, Federico Uliana, Martina Schifferer, Ali Rezaei, Lisa Marie Ramirez, Janine Hochmair, Rithika Sankar, Anusha Gopalan, Fridolin Kielisch, Henrick Riemenschneider, Viktoria Ruf, Carla Schmidt, Mikael Simons, Markus Zweckstetter, Susanne Wegmann, Tammaryn Lashley, Magdalini Polymenidou, Dieter Edbauer, Dorothee Dormann.

  Neuronal aggregates of Tau are a hallmark of Alzheimer's disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. Here, we demonstrate that Tau and TDP-43 mutually promote each other's condensation through direct interaction in vitro, forming irregularly-shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau mobility. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with these data, insoluble material extracted from AD patient brains with Tau/TDP-43 co-aggregates exhibits reduced Tau seeding compared to AD patient brains with Tau aggregates only. In contrast, patient-derived extracts from AD patient brains with Tau/TDP-43 co-aggregates are highly potent in seeding new TDP-43 aggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction between TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology in Alzheimer's disease patients.

Keywords:  Alzheimer’s Disease; Phase Separation; Seeding; TDP-43; Tau

DOI:  https://doi.org/10.1038/s44318-025-00590-2
Cells. 2025 Sep 29. pii: 1520. [Epub ahead of print]14(19):

Is TREM2 a Stretch: Implications of TREM2 Along Spinal Cord Circuits in Health, Aging, Injury, and Disease.

Tana S Pottorf, Elizabeth L Lane, Francisco J Alvarez.

  Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a receptor found in microglia within the central nervous system (CNS) as well as in several other cell types throughout the body. TREM2 has been highlighted as a "double-edged sword" due to its contribution to anti- or pro-inflammatory signaling responses in a spatial, temporal, and disease-specific fashion. Many of the functions of TREM2 in relation to neurological disease have been elucidated in a variety of CNS pathologies, including neurodegenerative, traumatic, and vascular injuries, as well as autoimmune diseases. Less is known about the function of TREM2 in motoneurons and sensory neurons, whose cell bodies and axons span both the CNS and peripheral nervous system (PNS) and are exposed to a variety of TREM2-expressing cells and mechanisms. In this review, we provide a brief overview of TREM2 and then highlight the literature detailing the involvement of TREM2 along the spinal cord, peripheral nerves and muscles, and sensory, motor, and autonomic functions in health, aging, disease, and injury. We further discuss the current feasibility of TREM2 as a potential therapeutic target to ameliorate damage in the sensorimotor circuits of the spinal cord.

Keywords:  Motor Neuron Disease (MND); Triggering Receptor Expressed on Myeloid Cells 2 (TREM2); macrophage; microglia; neuroinflammation; peripheral nerve injury (PNI); peripheral neuropathy; spinal cord injury (SCI); spinal reflexes

DOI:  https://doi.org/10.3390/cells14191520