bims-micgli 2026-06-28 papers

bims-micgli

Biomed News

on Microglia

Issue of 2026–06–28
twenty papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.
The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
Plasma Membrane Remodeling During Microglial Activation: A Hypothesis Linking Microglial Shape and Lipid Droplet Formation.
Reprogramming Neuroinflammation: Mitochondrial Targets and Immune Checkpoint Inhibitors in Alzheimer's Disease.
Microglial SWELL1 deficiency drives male-specific seizure vulnerability but paradoxical neuroprotection through impaired phagocytosis.
Antigen-specific adaptive immunity in Parkinson's disease: peripheral priming, brain-border reactivation and parenchymal injury.
C1qa□ muscularis macrophages maintain enteric synaptic homeostasis to regulate gastrointestinal motility.
Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.
KOLF2.1J iTF-Microglia: A standardized platform to study microglial transcriptional regulatory networks in CNS disease.
Microglial HMGB1 drives hyperacute neuroinflammation and acute neuronal injury following cerebral ischemia-reperfusion by shaping early microglial inflammatory responses.
Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis.
Glioma-intrinsic MAPK/ERK signaling promotes immunotherapy efficacy through T cell infiltration and interferon responses.
Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in AppNL -G-F Mice.
Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.
Mitochondrial stress response drives microglial senescence.
LPS-Induced Neuroinflammation in Neurodegenerative Diseases: A Double-Edged Sword?
Lysosomal ion homeostasis drives delayed hair cell death after aminoglycoside uptake.
Aβ- and tau-associated neuroinflammatory signatures in Alzheimer's disease.
A reappraisal of APOE genetic effects on Alzheimer's disease risk in the Japanese population: a meta-analysis.
Trem2 R47H mutation shows mild, but functionally divergent alterations in microglial phenotypes compared to Trem2 deficiency in aged AppNL-F knock-in mice.

J Neuroinflammation. 2026 Jun 25.

Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.

Yuta Morisaki, Nanaka Nomura, Motoki Ohshima, Miruto Matsuda, Okiru Komine, Takashi Okuda, Koji Yamanaka, Hidemi Misawa.

  Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclerosis (ALS) remain unexplored. Here, we investigated LAG-3, an inhibitory immune checkpoint receptor, in microglial regulation during ALS pathogenesis using SOD1G93A mice. LAG-3 expression was progressively upregulated in spinal cord microglia during disease progression, and LAG-3-high microglia exhibited a disease-associated microglia (DAM) transcriptional signature. Genetic deletion of LAG-3 produced a biphasic phenotype, with accelerated disease onset but significantly prolonged disease duration. LAG-3 deficiency enhanced inflammatory microglial responses at the early disease stage, whereas at the late stage it suppressed inflammatory signaling while selectively preserving phagocytic effector gene expression, demonstrating that LAG-3 dissociates the inflammatory and phagocytic modules within the DAM program in a stage-dependent manner. These transcriptional changes translated into enhanced phagocytic capacity in primary microglia and amelioration of the spinal cord environment through suppression of inflammatory pathways and restoration of oxidative phosphorylation. Our findings identify LAG-3 as a stage-dependent regulator of microglial functional states in ALS and support the concept that immune checkpoint molecules constitute a class of module-level regulators of microglial function in neurodegeneration.

Keywords:  Amyotrophic lateral sclerosis; Disease-associated microglia; Immune checkpoint; LAG-3; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-026-03919-8
Nat Neurosci. 2026 Jun 26.

The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.

Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.

Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.

DOI: https://doi.org/10.1038/s41593-026-02320-1
Glia. 2026 Aug;74(8): e70193

Plasma Membrane Remodeling During Microglial Activation: A Hypothesis Linking Microglial Shape and Lipid Droplet Formation.

G William Rebeck, Giorgi Shautidze, Jordy Sepulveda, Gracie S Healey, Priyanka S Narayan.

  Microglia are dynamic cells that respond both transcriptionally and morphologically to acute brain injury as well as to chronic neurodegenerative conditions. Upon activation, they become less ramified, more rounded, and accumulate intracellular lipid droplets. In this hypothesis paper, we propose that the formation of these lipid droplets supports the redistribution of plasma membrane lipids required during morphological remodeling. We rely on original and published studies of microglial morphology under conditions of aging, acute activation, and chronic activation. In ex vivo brain slices, microglia responded to either ATP or acute Aβ injections within minutes by extending their proximal processes toward the stimulus while simultaneously retracting their distal processes into their cell bodies. Chronic exposure to Aβ in mouse models of amyloid reduced microglial branching alongside a two- to three-fold loss of surface area. Transcriptomic analyses showed that activated microglia upregulate genes involved in fatty acid synthesis and fatty acid activation, both processes that are necessary in the production of triacylglycerol. Integrating these new and published analyses of microglia, we developed a hypothesis in which plasma membrane phospholipids are redistributed during acute activation and, during chronic activation, they are metabolized to triacylglycerol into lipid droplets. Tests of this hypothesis, through various pharmacological and genetic approaches, would contribute to our understanding of lipid droplets in cells that undergo substantial morphological changes.

Keywords:  fatty acids; lipid droplets; microglia; morphology; motility; plasma membrane; triacylglycerols

DOI:  https://doi.org/10.1002/glia.70193
Mol Neurobiol. 2026 Jun 22. pii: 712. [Epub ahead of print]63(1):

Reprogramming Neuroinflammation: Mitochondrial Targets and Immune Checkpoint Inhibitors in Alzheimer's Disease.

Nishant Kumar, Prince Ahad Mir, Gyamcho Tshering Bhutia, Preeti Chaudhary, Gurkiran Kaur, Qadir Alam, Sharad Daulatrao Pawar, Sukesh Kumar Gupta.

  Mitochondrial dysfunction and dysregulated microglial phenotypes are central contributors to the pathogenesis of Alzheimer's disease (AD), driving persistent neuroinflammation, synaptic loss, and impaired clearance of amyloid and tau aggregates. Disruptions in microglial mitochondrial metabolism lead to bioenergetic deficits, elevated oxidative stress, and shifts into maladaptive reactive states that exacerbate neuronal vulnerability. Recent insights into immune checkpoint pathways, including programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), highlight their roles in maintaining neuroimmune balance within the central nervous system (CNS). Although sustained engagement of these pathways in the peripheral compartment may contribute to immune exhaustion and reduced debris clearance, their CNS-resident roles in microglial homeostasis are protective, and this compartment-specific duality must be carefully considered in the design of targeted therapeutic strategies. Immune checkpoint inhibitors (ICIs), initially developed for oncology, are now being explored for their potential to modulate microglial responses, enhance amyloid removal, and mitigate neuroinflammation in AD. Emerging evidence suggests that combining ICIs with mitochondrial modulators may cooperatively support microglial homeostasis and potentially reprogram dysfunctional neuroimmune circuits, though direct combinatorial evidence in AD remains limited. Together, these findings provide a conceptual basis for considering a dual-targeted therapeutic framework for modulating neuroinflammation in AD. This review integrates current mechanistic insights into mitochondrial dysfunction and immune checkpoint signaling in AD and evaluates their translational potential as combined therapeutic strategies.

Keywords:  Alzheimer’s disease; CTLA-4; Immune checkpoint inhibitors; Mitochondria; Neuroinflammation; PD-1/PD-L1

DOI:  https://doi.org/10.1007/s12035-026-05983-w
JCI Insight. 2026 Jun 22. pii: e197980. [Epub ahead of print]11(12):

Microglial SWELL1 deficiency drives male-specific seizure vulnerability but paradoxical neuroprotection through impaired phagocytosis.

Abhijeet S Barath, Aastha Dheer, Laura Montier, Mekenzie M Peshoff, Emily Dale, Flavia Goche, Thanh Thanh Le Nguyen, Mastura Akter, FangFang Qi, Dimitrios Kleidonas, Lauren Harris, Sarah A Jewanee, Anthony D Umpierre, Dale B Bosco, Koichiro Haruwaka, Rajan Sah, Long-Jun Wu.

  The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type-specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional KO (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity, yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.

Keywords:  Epilepsy; Immunology; Neuroscience; Seizures

DOI:  https://doi.org/10.1172/jci.insight.197980
J Neuroinflammation. 2026 Jun 26.

Antigen-specific adaptive immunity in Parkinson's disease: peripheral priming, brain-border reactivation and parenchymal injury.

Kehao Wang, Ke Han, Yanqing Wang.

  Adaptive immune signals in Parkinson's disease (PD) now extend beyond descriptive neuroinflammation. Human genetic studies have implicated HLA variation, peripheral assays have detected α-synuclein- and PINK1-reactive T cells, neuropathology has identified early nigral CD8 + T-cell accumulation, and PD-relevant models have linked α-synuclein or mitochondrial antigen presentation to defined T-cell programs. This Review first places these findings in the modifying context of aging and then examines two antigen-specific routes across peripheral T-cell priming, central nervous system (CNS)-border reactivation or retention, and parenchymal effector injury. The α-synuclein/HLA-II/CD4 + T-cell route has the clearest support from human T-cell reactivity and border-associated macrophage (BAM)-dependent antigen presentation. The mitochondrial antigen/MHC-I/CD8 + T-cell route is strongest in PINK1-Parkin dysfunction and inflammatory settings, including CD8 + T-cell-mediated killing of Pink1 - / - dopaminergic neurons after mitochondrial antigen presentation. Trafficking mechanisms drawn from experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), viral encephalitis and cerebral malaria provide useful candidate pathways for PD studies, especially for post-vascular retention and glia-limitans passage. We also consider viral antigens as potential contributors to resident-memory-like CD8 + T-cell pools in the brain and discuss why PD models should be selected according to antigen axis, T-cell subset and immune context.

Keywords:  Adaptive immunity; Border-associated macrophages; Brain borders; PINK1; Parkin; Parkinson’s disease; T cells; α-synuclein

DOI:  https://doi.org/10.1186/s12974-026-03918-9
bioRxiv. 2026 Jun 08. pii: 2026.06.03.729640. [Epub ahead of print]

C1qa□ muscularis macrophages maintain enteric synaptic homeostasis to regulate gastrointestinal motility.

Mario D'Ambrosio, Juan Sebastian Ortiz Colmenares, Khaled Warasnhe, Yuanhang Liu, Mohamed H Eldesouki, Dokic Vladimir, Natalie R Wertish, Xin-Yi Chai, Sara Traserra, Trace A Christensen, Elisabetta Bigagli, Cristina Luceri, Keith A Sharkey, Madhusudan Grover, Marcel Jiménez, Arthur Beyder, Gianrico Farrugia, Gianluca Cipriani.

The enteric nervous system (ENS) is a complex peripheral neural network that coordinates gastrointestinal motility through highly organized synaptic communication. Although tissue-resident muscularis macrophages (MMs) closely associate with enteric neurons, whether they regulate enteric synaptic organization remains unknown. In the central nervous system (CNS), microglia sculpt neural circuits through complement-dependent synaptic remodeling, raising the possibility that analogous neuroimmune mechanisms operate in the gut. Here, we identify a previously unrecognized role for C1qa□ MMs in regulating enteric synaptic homeostasis and gastrointestinal motility. Using macrophage-specific constitutive and inducible C1qa deletion models, single-cell RNA sequencing, enteric synaptosome proteomics, physiology, and advanced imaging, we demonstrate that loss of MMs-derived C1qa increases enteric synaptic density without altering neuronal numbers. C1qa deficiency induced broad transcriptional changes in enteric neurons and macrophages, including altered synapse-associated, lysosomal, and endocytic programs. Proteomic analysis revealed that enteric synapses share a conserved molecular architecture with brain synapses while exhibiting distinct gastrointestinal-specific complement-associated synaptic networks enriched for structural and receptor-localization pathways. Functionally, macrophage-specific C1qa deletion altered excitatory and inhibitory enteric neurotransmission, enhanced cholinergic signaling, reduced nitrergic responses, and accelerated gastrointestinal transit, while smooth muscle responsiveness remained preserved. C1qa□ MMs displayed transcriptional and functional features consistent with a phagocytic synapse-remodeling phenotype, including enrichment of complement, lysosomal, and engulfment pathways. Loss of C1qa impaired macrophage phagocytic activity both in vitro and in vivo and was associated with synapse accumulation and altered macrophage morphology. Importantly, inducible deletion of C1qa in adulthood recapitulated the synaptic and motility phenotypes, demonstrating that C1qa□ MMs continuously regulate enteric synaptic organization beyond development. Together, these findings identify a complement-dependent neuroimmune mechanism that regulates enteric circuit organization and gut motility, establishing MMs as active modulators of adult ENS synaptic homeostasis.
Abstract Figure:

DOI: https://doi.org/10.64898/2026.06.03.729640
Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00673-X. [Epub ahead of print]45(7): 117595

Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.

Vanya Metodieva, Sybille Marchese, Pietro Esposito, John S H Danial, Andrea Di Falco, Suman De, David Klenerman, Juan A Varela.

  Amyloid-β 1-42 (Aβ42) aggregation is among the earliest pathological signs in Alzheimer's disease (AD). Here, we characterized Aβ42 species at several aggregation stages at the single-molecule level and examined their toxicity in murine organotypic brain slices, where we observed a stage-dependent recapitulation of multiple aspects of the cellular phase of AD. Aggregates formed during the lag phase of the Aβ42 aggregation elevated neuronal baseline Ca2+ levels and impaired long-term potentiation (LTP), while promoting microglial homeostatic exit and transition to disease-associated microglia (DAM) state. In contrast, aggregates enriched during the growth phase downregulated homeostatic microglial markers and induced TLR4-mediated microglial activation, cytokine production, and complement activation, leading to synaptic engulfment and severe disruption of neuronal activity. Together, these findings reveal that structurally distinct Aβ42 aggregate species engage different cellular and molecular pathways. This framework advances mechanistic understanding of amyloid toxicity in neurodegeneration and could inform the design of combination therapeutic strategies.

Keywords:  Alzheimer’s disease; CP: molecular biology; CP: neuroscience; DAM; TAK-242; TLR4; amyloid-beta; calcium imaging; inflammation; microglia; organotypic hippocampal slices; single-molecule imaging

DOI:  https://doi.org/10.1016/j.celrep.2026.117595
iScience. 2026 Jul 17. 29(7): 116412

KOLF2.1J iTF-Microglia: A standardized platform to study microglial transcriptional regulatory networks in CNS disease.

Brianne B Rogers, Ashlyn G Anderson, Ivan Rodriguez-Nunez, Samuel C Bartley, S Quinn Johnston, Jared W Taylor, Sarah K Meadows, Kimberly M Newberry, Richard M Myers, J Nicholas Cochran.

  Understanding transcriptional regulatory networks (TRNs) in microglia is essential for elucidating mechanisms underlying central nervous system (CNS) disorders. Human induced pluripotent stem cell (iPSC)-derived models enable mechanistic studies of microglia but often suffer from variability across lines. Here, we use the standardized KOLF2.1J iPSC line, engineered to inducibly express six transcription factors that allow rapid generation of microglia-like cells (iTF-microglia). We profile TRNs under homeostatic and inflammatory conditions and show that iTF-microglia resemble primary brain microglia at transcriptomic and epigenomic levels. Integrative analyses identify microglia-enriched candidate cis-regulatory elements (cCREs) and reveal dynamic enhancer remodeling during differentiation and stimulation with lipopolysaccharide (LPS) or interferon-gamma (IFNγ), involving NF-κB, IRF, and STAT transcription factors. TRNs active in iTF-microglia are enriched for genetic variants linked to Alzheimer's disease and related CNS disorders. These findings establish KOLF2.1J iTF-microglia as a reproducible, genetically tractable system for dissecting microglial gene regulation and TRN remodeling in disease.

Keywords:  neuroscience; stem cells research; techniques in neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.116412
Exp Neurol. 2026 Jun 22. pii: S0014-4886(26)00251-7. [Epub ahead of print]404 115886

Microglial HMGB1 drives hyperacute neuroinflammation and acute neuronal injury following cerebral ischemia-reperfusion by shaping early microglial inflammatory responses.

Ke Lei, Siyu Yang, Huoying Chen, Jiapei Dai, Qianjie Tan, Haoyu Wang, E Du, Jiawei Min, Jiawen Lei, Yi Luo, Yan Sun.

  High-mobility group box 1 (HMGB1) is a nuclear protein that can act as a major damage-associated molecular pattern after cerebral ischemia-reperfusion (I/R). However, the cell-type-specific contribution of microglial HMGB1 to early neuroinflammatory responses during the hyperacute phase of stroke is not fully understood. Here, we investigated the role of microglial HMGB1 in early inflammatory activation using a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and microglia-specific HMGB1 conditional knockout mice (HMGB1ΔMG). Acute neurological deficits, early ischemic lesion volume, microglial activation, inflammatory cytokine production, and neuronal integrity were evaluated at 6 h after reperfusion. In wild-type mice, hyperacute I/R induced rapid HMGB1 nuclear export, pronounced microglial activation with amoeboid-like morphology, increased TNF-α and IL-6 expression, and reduced TGF-β1 expression in vulnerable brain regions, including the medial prefrontal cortex and hippocampal CA1. Conditional deletion of microglial HMGB1 reduced early ischemic lesion volume, attenuated acute neurological deficits, dampened pro-inflammatory activation, decreased Iba1+iNOS+ cell accumulation, partially preserved or increased anti-inflammatory marker expression, and alleviated neuronal injury. These findings suggest that microglial HMGB1 acts as an important microglia-derived early trigger that contributes to hyperacute neuroinflammatory amplification and acute neuronal damage after I/R. Targeting HMGB1 mobilization in microglia may represent a promising strategy for attenuating early inflammatory amplification after ischemia-reperfusion.

Keywords:  Cerebral ischemia-reperfusion injury; HMGB1; Microglia; Microglial activation; Neuroinflammation

DOI:  https://doi.org/10.1016/j.expneurol.2026.115886
Acta Neuropathol. 2026 Jun 25. pii: 72. [Epub ahead of print]151(1):

Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis.

Lukas Lütje, J Q Alida Chen, Jörg Hamann, Joost Smolders, Inge Huitinga, Aletta M R van den Bosch.

  Multiple sclerosis (MS) shows pronounced pathological and clinical variability between individuals, reflecting differences in genetic susceptibility, inflammatory activity, and tissue repair. This variability complicates efforts to relate lesion pathology to clinical trajectories. In previous work in the Netherlands Brain Bank MS autopsy cohort (NBB-MS), we showed that relative proportions of different lesion types, lesion load, and microglia/macrophage activity score, associate with clinical severity, while also revealing marked inter-individual variability. Here, we extend these observations by examining whether selected donor-specific pathological features relate to genetic background, quantitative lesion type distributions, and clinical disease course, and thereby help contextualize this heterogeneity.Brain tissue from 287 NBB-MS donors was assessed for the presence of the donor-specific pathological features, namely perivascular cuffs, microglial nodules, broad rim lesions (BRLs), and remyelination efficiency. Perivascular cuffs and microglial nodules were more prevalent among carriers of the MS susceptibility allele HLA-DRB1*15:01 (rs3135388). BRLs and perivascular cuffs were enriched in carriers of the MS severity-associated SNP in the DYSF-ZNF638 locus (rs10191329). Perivascular cuffs associated with increased microglia/macrophage activation score and decreased age at death. Microglial nodules in the normal appearing white matter associated with a higher proportion of active lesions. BRLs were linked to increased proportions of active and mixed active/inactive lesions, higher brainstem lesion rate, and a higher age related MS severity score. Poor remyelination efficiency associated with a higher proportion of mixed active/inactive and inactive lesions, and a shorter disease duration.Together, these findings show that specific pathological features of donors relate to genetic risk, lesion type distribution, and clinical outcome. Integrating these donor-specific pathological features alongside lesion classification will enable a more biologically refined interpretation of post-mortem MS tissue study results and will improve understanding of inter-individual heterogeneity in MS.

Keywords:  Broad rim lesions; Microglia nodules; Multiple sclerosis; Neuropathology; Perivascular cuffs; Remyelination

DOI:  https://doi.org/10.1007/s00401-026-03040-3
Nat Commun. 2026 Jun 25.

Glioma-intrinsic MAPK/ERK signaling promotes immunotherapy efficacy through T cell infiltration and interferon responses.

Kwang-Soo Kim, Junyi Zhang, Víctor A Arrieta, Crismita Dmello, Elena Grabis, Yahaya A Yabo, Si Wang, Karl Habashy, Joseph Duffy, Junfei Zhao, Andrew Gould, Rishi Jain, Li Chen, Jian Hu, Irina Balyasnikova, Dhan Chand, Daniel Levey, Peter Canoll, Wenting Zhao, Peter A Sims, Raul Rabadan, Surya Pandey, Bin Zhang, Pouya Jamshidi, Catalina Lee-Chang, Dieter Henrik Heiland, Adam M Sonabend.

Glioblastoma (GBM) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) only showing efficacy in some patients, while the mechanisms governing therapeutic responsiveness are poorly defined. Although MAPK/ERK signaling correlates with survival following ICB, its causal role and mechanisms underlying tumor immunogenicity remain unclear. Here, we perform in vivo kinome-wide CRISPR/Cas9 screens in murine gliomas where we identify RAF-MEK-ERK axis as the strongest modulators of glioma susceptibility to anti-programmed cell death protein 1 (anti-PD-1) therapy and CD8+ T cell recognition. Experimentally-induced ERK phosphorylation (p-ERK) enhances survival after anti-PD-1 and anti-CTLA-4 therapy, leading to durable antitumor immunity upon rechallenge. Additionally, glioma cell p-ERK promotes increased interferon responses and T cell infiltration. Notably, BRAF/MEK inhibition disrupts interferon programs and tumor-microglia interactions in BRAFV600E ex vivo in human GBM/brain slice cultures. Our findings elucidate that tumor-intrinsic MAPK/ERK promotes immunotherapy response, interferon responses, T cell tumor infiltration, and GBM cell-microglia interactions.

DOI: https://doi.org/10.1038/s41467-026-74124-7
Glia. 2026 Aug;74(8): e70192

Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in AppNL -G-F Mice.

Ryan J Bevan, Emily Maguire, Eilish Mackinnon, Elisa Salis, Thomas Phillips, Elena Simonazzi, Marieta Vassileva, Nicholas D Allen, Julie Williams, Philip R Taylor.

The Alzheimer's disease protective P522R PLCG2 coding variant (rs72824905) is downstream of TREM2, but how it confers disease protection is poorly understood. Using a Plcg2-R522 knock-in mouse and Plcg2-P522 control on both wildtype and Alzheimer's disease-like AppNL-G-F amyloidosis mouse backgrounds, aged mice were assayed for amyloid load, microglial activity, and synaptic integrity. In the absence of Alzheimer's disease-like pathology, the R522 variant increased microglial coverage and was associated with reduced ramification complexity, fewer terminal points, and elevated lysosomal CD68 expression. On the AppNL-G-F background, total amyloid burden was unaffected, but expression of the R522 variant led to increased plaque compaction compared to the P522 common variant. The protective R522 variant was also associated with: enhanced microglial engagement with less compact amyloid plaques; reduced microglial localisation around highly compacted plaques; protection from amyloid-induced synapse loss; and decreased engulfment of synaptic material by microglia. Our data indicate a significant direct PLCγ2 role in controlling microglial-plaque interactions and synaptic protection downstream of amyloid deposition, prioritizing it as a therapeutic target, potentially as an adjunct to other approaches, such as those targeting amyloid.

DOI: https://doi.org/10.1002/glia.70192
Int J Mol Sci. 2026 Jun 20. pii: 5580. [Epub ahead of print]27(12):

Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.

Wei Shao, Kai Wang, Yongchao Liu, Haojia Zhang, Zijin Sun, Rui Zhou.

  The mammalian brain fundamentally relies on precise lipid homeostasis to maintain structural integrity and complex neural signaling. Emerging evidence positions lipid metabolism reprogramming not merely as a secondary pathological byproduct but as a core initiating driver of age-related neurodegenerative diseases. This review systematically evaluates the mechanisms of cerebral lipid dyshomeostasis during brain aging, highlighting glial cells as the central mediators of this pathological cascade. We comprehensively dissect the age-associated "lipid drift", emphasizing apolipoprotein E (APOE)-induced cholesterol transport defects and lipid raft pathology, the accumulation of lipid droplets that triggers microglial metabolic stress (LDAMs), and ceramide-driven neuronal apoptosis coupled with the exosome-mediated propagation of pathogenic proteins. Furthermore, we map these aberrant lipid networks to specific pathological signatures in Alzheimer's, Parkinson's, and demyelinating diseases. Finally, we critically evaluate promising therapeutic interventions, including nutritional strategies, LXR/RXR agonists, and nanotechnology-enabled delivery systems designed to bypass the blood-brain barrier. By integrating high-throughput lipidomics for early diagnostic biomarker discovery, we underscore the translational imperative of restoring cerebral lipid homeostasis as a disease-modifying strategy for neurodegeneration.

Keywords:  apolipoprotein E (APOE); brain aging; cerebral lipid homeostasis; lipid metabolism reprogramming; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms27125580
Nat Neurosci. 2026 Jun 26.

Mitochondrial stress response drives microglial senescence.

Luca Peruzzotti-Jametti, Stefano Pluchino.

DOI: https://doi.org/10.1038/s41593-026-02264-6
Mol Neurobiol. 2026 Jun 20. pii: 711. [Epub ahead of print]63(1):

LPS-Induced Neuroinflammation in Neurodegenerative Diseases: A Double-Edged Sword?

Alaleh Mohammadi, Ali Aghajan, Morteza Alipour, Avin Ghorbani, Samim Momennejad Limoodehi, Mojtaba Hedayati Ch.

  Lipopolysaccharide (LPS), a glycolipid endotoxin derived from Gram-negative bacteria, activates Toll-like receptor 4 (TLR4) signaling in microglia and astrocytes, initiating neuroimmune cascades characterized by pro-inflammatory cytokine release, oxidative stress, and glial reactivity. Chronic or high-dose LPS exposure promotes sustained neuroinflammation, blood-brain barrier disruption, impaired amyloid-β (Aβ) clearance in Alzheimer's disease (AD), and exacerbated α-synuclein pathology in Parkinson's disease (PD). In contrast, low-dose or intermittent exposure may promote adaptive neuroimmune responses characterized by regulated glial signaling and enhanced neuronal resilience. Emerging evidence suggests that these divergent outcomes are shaped by the biological context of LPS exposure, including dose, duration, route of administration, and host inflammatory status. The gut-brain axis further modulates these effects by linking peripheral inflammatory signals and microbial metabolites to central nervous system responses. Despite growing mechanistic insight, important knowledge gaps remain, particularly regarding the translational relevance of region-specific glial responses in humans. Improved understanding of context-dependent LPS signaling may help explain inconsistencies across experimental studies, refine neuroinflammation models, and support the development of therapeutic strategies targeting TLR4 signaling, autophagy, and gut-brain interactions. Collectively, current evidence suggests that LPS-induced neuroinflammation exists along a dynamic continuum, with transient immune activation potentially supporting adaptive neuroimmune responses, whereas chronic or dysregulated exposure promotes sustained neuroinflammation and progressive neurodegenerative changes.

Keywords:  Alzheimer's disease; Gut-brain axis; LPS; Neuroimmune adaptation; Neuroinflammation; Parkinson's disease; TLR4

DOI:  https://doi.org/10.1007/s12035-026-06004-6
bioRxiv. 2026 Jun 14. pii: 2026.06.10.731244. [Epub ahead of print]

Lysosomal ion homeostasis drives delayed hair cell death after aminoglycoside uptake.

Francisco A Barros Becker, Ananya Cholkar, Tor H Linbo, David W Raible.

Aminoglycoside ototoxicity has been widely reported and remains an important public health issue. Unfortunately, the molecular mechanisms of ototoxicity are not well understood. Here, we report the lysosome compartment as the main driver of delayed cell death triggered by aminoglycosides. By labeling early and late endosomes we show that endocytosis is not an significant path of aminoglycoside uptake. Instead, we show that aminoglycosides are delivered to lysosomes primarily through autophagy. Hair cells can be protected from damage by activation of the dual function lysosomal Two-Pore-Channel 2 (TPC2), stimulated by NAADP agonist but not by phosphoinositide PI(3,5,)P2 agonist. These treatments neutralize lysosomal pH. Moreover, luminal pH changes are also accompanied by changes in ferrous iron availability, though classical ferroptosis inhibitors do not prevent a delayed hair cell death. These findings reveal that lysosomal-driven delayed hair cell death is ferroptosis independent, suggesting that toxicity relies on a distinct mechanism that based on the internal conditions of the lysosomal compartment.

DOI: https://doi.org/10.64898/2026.06.10.731244
Alzheimers Dement (N Y). 2026 Apr-Jun;12(2):12(2): e70275

Aβ- and tau-associated neuroinflammatory signatures in Alzheimer's disease.

Bruna Bellaver, Guilherme Povala, Marco Antônio De Bastiani, Ilaria Pola, Pamela C L Ferreira, Guilherme Bauer-Negrini, João Pedro Ferrari-Souza, Douglas T Leffa, Firoza Z Lussier, Joseph Therriault, Nesrine Rahmouni, Jenna Stevenson, Stijn Servaes, Riddhi Patira, Serge Gauthier, Dana L Tudorascu, Thomas K Karikari, Nicholas Ashton, Kaj Blennow, Henrik Zetterberg, Eduardo R Zimmer, Andrea L Benedet, Pedro Rosa-Neto, Tharick A Pascoal.

   INTRODUCTION: Neuroinflammation is increasingly recognized as a key contributor to Alzheimer's disease (AD) progression, with distinct responses linked to amyloid beta (Aβ) and tau pathology. Two detrimental waves of neuroinflammation have been proposed, the first during early Aβ accumulation, and the second during widespread tau deposition. However, the neuroinflammatory signatures associated with each phase remain unclear.
METHODS: We studied 63 individuals who underwent Aβ and tau positron emission tomography imaging along with cerebrospinal fluid profiling of 368 inflammation-related proteins. Protein contrasts between cognitively unimpaired Aβ-negative and Aβ-positive individuals defined the signature of the Aβ phase, while comparisons between cognitively impaired Aβ-positive individuals with early versus late tau pathology characterized the tau phase. Gene Ontology enrichment identified biological processes associated with differentially expressed proteins.
RESULTS: During the Aβ phase, 34 proteins were downregulated and mapped to 157 biological processes, including Toll-like receptor signaling, nuclear factor kappa beta activation, and cytokine production. The tau phase showed upregulation of 23 proteins associated with 82 biological processes enriched in adaptive immune responses. A set of 48 biological processes and three proteins including interleukin 4 receptor, cystosolic phospholipidase A2, and secretoglobin family 3A member 2 showed opposite regulation patterns, being downregulated in the Aβ phase and upregulated in the tau phase.
DISCUSSION: Our results revealed distinct neuroinflammatory signatures and biological processes associated with Aβ- and tau-dominant stages of AD. The reversal in protein expression patterns across these stages underscores the need for stage-specific neuroimmune therapeutic strategies.

Keywords:  Alzheimer's disease; biomarkers; neuroinflammation; positron emission tomography

DOI:  https://doi.org/10.1002/trc2.70275
Mol Neurodegener. 2026 Jun 24. pii: 33. [Epub ahead of print]21(1):

A reappraisal of APOE genetic effects on Alzheimer's disease risk in the Japanese population: a meta-analysis.

Akinori Miyashita, Norikazu Hara, Ai Obinata, Tamao Tsukie, Mai Hasegawa, Takanobu Ishiguro, Kensaku Kasuga, Masataka Kikuchi, Tadafumi Hashimoto, Takahisa Kanekiyo, Takeshi Ikeuchi.

Our meta-analysis demonstrates that the risk effect of APOE-e4*4 relative to APOE-e3*3 for Alzheimer's disease in the Japanese population is approximately 12-15-fold, comparable to that reported in Caucasian populations, rather than greater than 20-fold as previously reported.

DOI: https://doi.org/10.1186/s13024-026-00963-z
Exp Neurol. 2026 Jun 24. pii: S0014-4886(26)00259-1. [Epub ahead of print] 115894

Trem2 R47H mutation shows mild, but functionally divergent alterations in microglial phenotypes compared to Trem2 deficiency in aged AppNL-F knock-in mice.

Keiro Shirotani, Daisuke Hatta, Kaori Watanabe, Takashi Saito, Takaomi C Saido, Nobuhisa Iwata.

  The TREM2 R47H variant increases the risk of Alzheimer's disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the AppNL-F background and compared it with a Trem2 knockout (KO) line to assess the degree of TREM2 functional impairment. Accumulation of amyloid β 42 and formation of dystrophic neurites were increased in Trem2 KO mice but not in Trem2 R47H KI mice at 18 or 24 months. qPCR and transcriptomic analyses revealed Trem2 KO mice showed deficits in upregulation of microglial genes while Trem2 R47H KI mice showed a response similar to control mice. Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice. Among the differentially expressed genes, Pmel and Gpnmb were or tended to be downregulated in Trem2 R47H KI as well as in Trem2 KO mice indicating their involvement in AD pathogenesis. These results clearly indicate that the TREM2 R47H variant confers a mild, rather than null, effect on microglial alterations during AD development and that Trem2 R47H KI mice should be used to understand pathological mechanism elicited by TREM2. Further identification and characterization of genes differentially expressed in Trem2 R47H KI mice will provide important insights into how the TREM2 risk variant modulates Alzheimer's disease-related pathology.

Keywords:  Alzheimer's disease; Amyloid β; Dystrophic neurite; Gene expression; Microglia; Risk gene; TREM2

DOI:  https://doi.org/10.1016/j.expneurol.2026.115894