bims-microg 2026-08-16 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–08–16
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln

Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.
Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.
Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and neuronal dysfunction.
VlPAG/DRN Microglia Drive Neuropathic Pain-Induced Depression via a Defined Neuroimmune Axis.
Multifunctional theranostic nanocarrier platform for microglia-selective cytochalasin D delivery to modulate neuroinflammation after acute brain injuries.
Activated microglial phenotypes in the hippocampal CA2 subfield are implicated in Lewy body disease progression.
Histone H3K27M variants determine myeloid subset dependencies and immune reprogramming in diffuse midline glioma.
Lysosomal channel TPC2 modulates microglia-endothelial signaling in choroidal angiogenesis.
SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.
Deletion of RGS5 attenuates high-fat diet-induced cerebrovascular pathology and associated spatial memory deficits.
Differential consequences of traumatic brain injury in male rat hippocampus hemispheres and the beneficial effect of neuropeptide Y.
COVID-19 Amplifies Sex-Specific Dopamine and Glial Responses in a Parkinson's Disease Mouse Model.
Distinct Transposable Element Transcript Patterns in Microglia Across Aging and Alzheimer's Disease.
Tgf-β receptor signaling cell-intrinsically controls conserved microglia homeostatic maturation during zebrafish development.
APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.
An ApoE-Associated Low-Inflammatory Microglial State Emerges After Inflammatory Challenge in Alzheimer's Disease Mice.
Cholesterol Drives IFITM3+ Microglia Activation and Induces STING Mediated Neuroinflammation After Ischemic Stroke.
Modelling Ferroptosis in a Human Microglial Line by Sequential Exposure to Iron and GPX4 Inhibition.
SGLT2i Canagliflozin Exerts Neuroprotection in Diabetic Retinopathy by Inhibiting Microglial Proinflammatory Cytokine Release by Downregulating the TLR4/NF-κB/NLRP3 Pathway.

Nat Genet. 2026 Aug 11.

Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.

Donghoon Lee, James M Vicari, Christian Porras, Collin Spencer, Milos Pjanic, Xinyi Wang, Seon Kinrot, Philipp Weiler, Roman Kosoy, Jaroslav Bendl, Prashant N M, Konstantina Psychogyiou, Periklis Malakates, Evelyn Hennigan, Jennifer Monteiro Fortes, Shiwei Zheng, Karen Therrien, Deepika Mathur, Steven P Kleopoulos, Zhiping Shao, Stathis Argyriou, Marcela Alvia, Clara Casey, Aram Hong, Kristin G Beaumont, Robert Sebra, Christopher P Kellner, David A Bennett, Guo-Cheng Yuan, Georgios Voloudakis, Fabian J Theis, Vahram Haroutunian, Gabriel E Hoffman, John F Fullard, Panos Roussos.

Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.

DOI: https://doi.org/10.1038/s41588-026-02716-6
Nat Commun. 2026 Aug 12. pii: 8173. [Epub ahead of print]17(1):

Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.

Brittany M Hemmer, Sarah M Philippi, Ana Catarina Ferreira, Samuele F Petridis, Annie Phan, Joseph M Castellano.

There is little understanding of how aging serves as the strongest risk factor for several neurodegenerative diseases. Microglia undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear. The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function. We show that TIMP2 deletion in mice exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, changes in lysosomal-associated markers and phagocytosis, and elevated levels of stress and inflammatory proteins in the brain extracellular space measured by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increases microglial CD68 and alters myelin phagocytosis. Treating aged mice with TIMP2 reverses several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.

DOI: https://doi.org/10.1038/s41467-026-74906-z
Neuron. 2026 Aug 11. pii: S0896-6273(26)00577-5. [Epub ahead of print]

Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and neuronal dysfunction.

Bangyan Liu, Matthew Mahoney, Yilin Feng, Maria Telpoukhovskaia, Alice Maria Giani, Eileen Ruth Torres, Lihong Zhan, Pearly Ye, Jingjie Zhu, Nessa R Foxe, Daphne Zhu, Xinran Tong, Deepak Srivastava, Christina V Theodoris, Shiaoching Gong, Mingrui Zhao, Li Fan, Li Gan.

  Aging is the major risk factor for neurodegenerative disease, yet the mechanisms linking physiological aging to brain dysfunction remain unclear. We investigated the brains of telomere-shortened mice and observed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single-nucleus RNA sequencing (snRNA-seq) revealed accelerated glial aging and elevated microglial senescence pathways. In a senescence model of human induced pluripotent stem cell (iPSC)-derived microglia, delta-like non-canonical Notch ligand 1 (DLK1) was identified as a novel senescence-associated ligand. Soluble DLK1 (sDLK1) was increased in the cerebrospinal fluid of telomere-shortened and naturally aged mice, and this increase was eliminated by microglial depletion. In vivo elevation of sDLK1 caused hypomyelination and blocked oligodendrocyte lineage progression, and these effects demonstrate the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.

Keywords:  DLK1; SASP; microglia; neuronal activity; oligodendrocyte; senescence; telomere erosion

DOI:  https://doi.org/10.1016/j.neuron.2026.07.021
Adv Sci (Weinh). 2026 Aug 11. e77071

VlPAG/DRN Microglia Drive Neuropathic Pain-Induced Depression via a Defined Neuroimmune Axis.

Jing Yang, Bing-Jie Tang, Jia-Yi Li, Shu-Lan Xie, Shumin Duan, Junping Chen, Shengmei Zhu, Zhen-Zhong Xu.

  Neuropathic pain is frequently comorbid with anxiety and depression, yet the mechanisms linking immune signaling to affective brain circuits remain poorly understood. Here, we identify a neuroimmune circuit in which peripheral nerve injury activates microglia in the midbrain ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DRN), triggering an NLRP3-IL-1β-dependent inflammatory cascade. Direct optogenetic or chemogenetic activation of vlPAG/DRN microglia is sufficient to drive negative affective behaviors. We show that local VGLUT2+ glutamatergic neurons (vlPAG/DRNGlu) are the principal IL-1R1-expressing targets; IL-1β activates these neurons to drive anxiety- and depression-like states. Conversely, microglia-specific Nlrp3 deletion or local IL-1R1 blockade prevents neuropathic pain-induced affective deficits. Furthermore, circuit mapping and functional manipulation reveal an excitatory vlPAG/DRNGlu to the bed nucleus of the stria terminalis (BNSTGABA) pathway that is both sufficient to induce and required to maintain the affective component of neuropathic pain. Together, our findings delineate a microglia-vlPAG/DRNGlu-BNSTGABA axis that translates peripheral injury into maladaptive emotional states, revealing a discrete neuroimmune circuit substrate for mood comorbidity in chronic pain.

Keywords:  biology; chemistry; medicine

DOI:  https://doi.org/10.1002/advs.77071
Biomaterials. 2026 Jul 29. pii: S0142-9612(26)00519-3. [Epub ahead of print]337 124495

Multifunctional theranostic nanocarrier platform for microglia-selective cytochalasin D delivery to modulate neuroinflammation after acute brain injuries.

Sabri E M Sahnoun, Rozina Noristani, Paolo Alimonti, Jonas Pes, Lara Gubeljak, Annika Szymura, Shaista Ilyas, Eren Arik, Alexandru Florea, Eva M Buhl, Bernd Neumaier, Sanjay Mathur, Jörg B Schulz, Felix M Mottaghy, Pardes Habib.

  Targeting microglia to modulate neuroinflammation after acute brain injuries (ABIs) is promising but limited by poor blood-brain barrier (BBB) penetration and systemic toxicity of candidate agents. In addition, multifunctional platforms combining targeted therapy with real-time traceability remain limited. We developed and characterized a multifunctional theranostic, folate-functionalized, polydopamine (PDA)-coated mesoporous silica nanoparticle (FA-NP) system for microglia-selective delivery and intracellular release of cytoskeleton inhibitor Cytochalasin D (CytoD). FA-NPs exhibited ideal physicochemical properties for parenchymal brain accumulation and pH-sensitive PDA shells enabled intracellular retention and gradual degradation. Using radiolabeled and fluorescein-isothiocyanate-functionalized FA-NPs, SPECT/CT imaging, γ-counting, autoradiography, and immunohistochemistry confirmed parenchymal brain accumulation with cellular uptake following systemic administration. Activated microglia upregulated folate receptors (FOLR1/2) and internalized FA-NPs via FOLR-mediated, dynamin-dependent endocytosis. CytoD-loaded FA-NPs (FA-NP[CytoD]) significantly reduced microglial migration, phagocytosis, ROS production, and proinflammatory cytokines, outperforming molecular CytoD while exhibiting notably lower toxicity compared to both CytoD and unfunctionalized particles. In organotypic brain slice models of hypoxia-reoxygenation and traumatic injury, FA-NP[CytoD] reduced inflammation at 24 and 96 h. Systemic administration enabled brain accumulation with clearance over time. Together, this multifunctional theranostic platform integrates selective microglial targeting, controlled drug release, and multimodal imaging, offering translational potential for ABIs.

Keywords:  Nanomedicine; Neurotherapeutics; Precision medicine; Stroke; TBI; Targeted drug delivery; Theranostics

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124495
Acta Neuropathol. 2026 Aug 08. pii: 17. [Epub ahead of print]152(1):

Activated microglial phenotypes in the hippocampal CA2 subfield are implicated in Lewy body disease progression.

Esteban Luna, Katheryn A Q Cousins, Sheina Emrani, Sharon X Xie, Winifred Trotman, Noah Capp, Philip Sabatini, Parham Pouladvand, EunRan Suh, Vivianna M Van Deerlin, Daniel Weintraub, Alice S Chen-Plotkin, Edward B Lee, David J Irwin.

  Histopathologic staging models of neuronal α-synuclein pathology (n-asyn) in Lewy body disease (LBD) seldom evaluate brain regions with direct synaptic connectivity to model the role of microglial processes. We address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, n-asyn is associated with activated microglial phenotypes. We selected a cohort of autopsy-confirmed LBD patients and minimal age-related copathologies (n = 62) and a control cohort of cognitively healthy patients with isolated hippocampal tau accumulation (i.e., primary age-related tauopathy, PART; n = 12), to control for neurodegenerative pathology without amyloid plaques. We immunostained consecutive hippocampal sections for n-asyn and established markers of activated microglial phenotypes, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied (%AO) of each marker in 6 hippocampal subfields to compare and correlate microglial morphologic and proteomic activation phenotypes between cohorts and used linear mixed effects models to compare the %AO between subfields while covariying for demographics. We also constructed groups of n-asyn restricted to the cornu ammonis (CA) 2-3 subfields (Focal Subtype) or widespread n-asyn within additional subfields (Widespread Subtype) to model hypothesized n-asyn spread within the intrahippocampal circuit. LBD patients exhibited increased HLA-DR and CD68%AO in most hippocampal subfields compared with PART. In LBD patients, all microglial markers were the highest in the CA2. CA2 n-asyn correlated with HLA-DR and CD68 but not Iba1%AO. Patients classified as Widespread Subtype had worse cognitive impairment and increased CA2 HLA-DR and CD68%AO. CA2 HLA-DR and CD68%AO correlated with distal n-asyn in retrograde, but not anterograde connected subfields. Our data show that activated microglial phenotypes in the CA2 of LBD patients are associated with worse clinical outcomes and retrograde n-asyn transmission. These data suggest that measures of microglial states can refine LBD histopathological progression models.

Keywords:  Hippocampus; Lewy body dementia; Lewy body disease; Lewy pathology; Microglia; α-Synuclein

DOI:  https://doi.org/10.1007/s00401-026-03065-8
Proc Natl Acad Sci U S A. 2026 Aug 18. 123(33): e2537768123

Histone H3K27M variants determine myeloid subset dependencies and immune reprogramming in diffuse midline glioma.

Montserrat Puigdelloses Vallcorba, Kavita Rawat, Nishant Soni, Angela DiMauro, Jacqueline D Chu, Wes Thomason, Glaucia C Furtado, Maya Strahl, Junyan Wu, Tanvi Joshi, Angelo Angione, Gonzalo Piñero, Oren J Becher, James L Ross, Alexander M Tsankov, Sergio A Lira, Dolores Hambardzumyan.

  Diffuse midline gliomas (DMGs) are highly aggressive, WHO grade 4 glial tumors that arise in midline central nervous system structures and are defined by K27M mutations in histone H3 genes. These K27M mutations shape intratumoral myeloid cell composition in DMG. In H3.1K27M DMGs, genetic ablation of monocyte recruitment reshapes the tumor microenvironment (TME) by reducing monocyte-derived macrophages (MDMs) and increasing microglia and neutrophil presence, with overall survival remaining unchanged, indicating compensatory myeloid remodeling is occurring. Here, by using CRISPR/Cas9-based genome editing, we generated a mouse model deficient for CCR1/CCR2/CCR3/CCR5 (Δ1235). Using this strain, we effectively abolished monocyte and MDM infiltration and reversed compensatory recruitment of CCR1+ neutrophils. Abolishing MDMs in tumors skewed remaining neutrophils and microglia toward a homeostatic state, reduced expression of immune checkpoint molecules on T cells, and extended the survival of H3.1K27M DMG-bearing mice. In contrast, H3.3K27M DMG showed independence from MDM recruitment, suggesting reliance on other TME-driven signaling. Last, H3.1K27M DMGs exhibited reduced microglia presence and a dose-dependent increase in MDM infiltration postirradiation. MDM depletion did not further enhance radiation efficacy, potentially due to compensatory recruitment of classical neutrophils. Collectively, these data reveal histone mutation-specific myeloid dependencies in DMG, highlighting MDM-independent mechanisms in H3.3K27M tumors and MDM-dependent pathways in H3.1K27M tumors.

Keywords:  Glioma; microglia; monocyte; neutrophil; pediatric

DOI:  https://doi.org/10.1073/pnas.2537768123
Angiogenesis. 2026 Aug 12. pii: 58. [Epub ahead of print]29(4):

Lysosomal channel TPC2 modulates microglia-endothelial signaling in choroidal angiogenesis.

Yi Lu, Alice Reschigna, Franz Kynast, Zhuo Yang, Maximillian Gerhardt, Pavel Kielkowski, Siegfried Priglinger, Martin Biel, Stylianos Michalakis.

  Pathological choroidal neovascularization underlies vision loss in neovascular age-related macular degeneration (nAMD), yet the molecular regulators coordinating vascular and immune components remain incompletely defined. Here, we investigated the role of the endolysosomal cation channel, two-pore channel 2 (TPC2) in choroidal angiogenesis. Loss of TPC2 in mice markedly reduced ex vivo choroidal sprouting, while pharmacological activation enhanced vascular growth. Mechanistically, Tpc2-deficiency led to downregulation of multiple microglia-derived pro-angiogenic factors and impaired the ability of the microglial secretome to stimulate neovascularization. In choroidal vascular cells, TPC2 loss attenuated NF-κB/MAPK signaling pathways. Tpc2-deficiency is also associated with lysosomal secretion of cathepsins, especially CTSD, resulting in decreased extracellular proteolytic activity and impaired paracrine regulation of angiogenesis. Extending these findings to human cells, TPC2 knockout in iPSC-derived endothelial cells impaired migration, tube formation, and CTSD activity in the secretome, mirroring the murine phenotype. Together, these results establish TPC2 as one of the regulators of lysosome-mediated choroidal angiogenesis, highlighting its potential as a therapeutic target in nAMD.

Keywords:  Cathepsins; Choroidal neovascularization; Lysosome; Microglia; TPC2

DOI:  https://doi.org/10.1007/s10456-026-10082-4
Brain Behav Immun. 2026 Aug 10. pii: S0889-1591(26)00701-4. [Epub ahead of print] 106953

SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.

Xiaoman Dai, Ziling Ye, Xujun Zhang, Yufei Huang, Chen Wang, Yanling Liu, Boya Gao, Jing Zhang, Xiaochun Chen.

  Metabolic dysfunction in microglia is increasingly recognized as a core driver of Alzheimer's disease (AD) pathogenesis, and yet the underlying mechanisms remain elusive. Here, we identified salt-inducible kinase 2 (SIK2) as a critical metabolic checkpoint that was downregulated in microglia across the AD mouse models (5 × FAD, APP/PS1, and SAMP8). We found that a loss of SIK2 in microglia induced a pro‑inflammatory phenotype, thus impairing amyloid β-protein (Aβ) phagocytosis and rewiring glucose and lipid metabolism toward enhanced glycolysis and lipid accumulation. Mechanistically, SIK2 directly interacted with the histone acetyltransferase P300; SIK2 deficiency increased the activity of P300, elevating H3K9 acetylation and H4K8/12 lactylation at promoters of metabolic genes. The microglia‑specific SIK2 overexpression in the 5 × FAD mice mitigated cognitive deficits, Aβ pathology, neuroinflammation, and aberrant histone modifications. A pharmacological inhibition of P300 regained these protective effects. Our findings highlight the SIK2-P300 epigenetic axis as a key regulator of the metabolic homeostasis in microglia and a potential therapeutic target for AD treatments.

Keywords:  Acetylation; Alzheimer’sdisease; Lactylation; Metabolic reprogramming; Neuroinflammation; P300; Salt-inducible kinase 2

DOI:  https://doi.org/10.1016/j.bbi.2026.106953
Brain Behav Immun. 2026 Aug 10. pii: S0889-1591(26)00698-7. [Epub ahead of print]138 106950

Deletion of RGS5 attenuates high-fat diet-induced cerebrovascular pathology and associated spatial memory deficits.

Osama F Elabi, Shubhangini Tiwari, Alba M Garcia-Serrano, Robert Carlsson, Carlos Noriega Polo, Luis A Fonseca-Fonseca, João M N Duarte, Gesine Paul.

  Diet-induced metabolic dysregulation is associated with cerebral microvascular pathology contributing to cognitive decline and vascular dementia. These alterations include blood-brain barrier (BBB) leakage, pericyte dysfunction, aberrant angiogenesis and perivascular neuroinflammation. Restoration of BBB integrity has been achieved in other conditions by targeting pericytes, for example through knockout of Regulator of G-protein Signaling 5 (RGS5), a sensor protein for hypoxia and oxidative stress highly enriched in these cells. It remains unclear whether deletion of RGS5 can provide vascular protection in conditions of chronic metabolic stress and prevent cognitive impairment despite ongoing metabolic dysfunction. We used constitutional RGS5 knockout (KO) mice and wildtype (WT) controls fed a standard or high-fat diet (HFD) for 23 weeks to induce metabolic dysfunction, confirmed by weight gain, insulinemia and impaired glucose tolerance. BBB leakage, vascular pathology (vessel density, branching, pericyte density and coverage), microglial activation and microglia-capillary interactions were analyzed using immunohistochemistry. Spatial memory was evaluated using the novel object location test. HFD induced obesity, glucose intolerance and insulin resistance in all mice. In WT but not RGS5-KO mice, HFD caused BBB leakage, immature angiogenesis and pericyte activation. RGS5 deletion also prevented microglial activation and enhanced interactions between resting microglia and striatal vessels. Importantly, HFD-induced impairment of spatial memory was prevented in KO mice. These data suggest that deletion of RGS5 preserves BBB integrity, maintains microvascular homeostasis, reduces neuroinflammation and ameliorates memory decline in diet-induced metabolic dysfunction. These findings highlight RGS5 as a potential therapeutic target and emphasize microvascular dysfunction as a contributor to HFD-induced cognitive decline.

Keywords:  Blood-brain barrier; Cognition; High-fat diet-induced obesity; Insulin resistance; Metabolic dysfunction; Pericyte; Regulator of G-protein signaling 5

DOI:  https://doi.org/10.1016/j.bbi.2026.106950
Brain Behav Immun. 2026 Aug 10. pii: S0889-1591(26)00700-2. [Epub ahead of print] 106952

Differential consequences of traumatic brain injury in male rat hippocampus hemispheres and the beneficial effect of neuropeptide Y.

Ricardo A Leitão, José L Alves, Ana L Bernardo, Anabela Mota-Pinto, Ana Paula Silva.

  Traumatic brain injury (TBI) initiates a complex cascade of secondary injury mechanisms, including neurovascular dysfunction, neuroinflammation, and glial activation, which progressively contribute to long-term neurological deficits. Although the primary mechanical insult is typically unilateral, secondary pathological processes can extend beyond the impact site. However, the spatiotemporal evolution of these bilateral alterations remains poorly understood. Neuropeptide Y (NPY) is an endogenous neuromodulator with anti-inflammatory and neuroprotective properties, making it a promising candidate for limiting secondary brain injury. Here, we characterized the bilateral hippocampal response to experimental TBI and evaluated whether early intranasal NPY administration post-TBI attenuates neurovascular and neuroinflammatory alterations while improving behavioral outcomes. Male Sprague-Dawley rats were subjected to a closed-head weight-drop model of TBI and treated intranasally with NPY (100 μg/animal) or vehicle 30 min after injury. Molecular, histological, and behavioral analyses were performed 48 h and 7 days post-injury. We concluded that TBI induced distinct spatiotemporal pathological responses in the hippocampi. The ipsilateral hippocampus exhibited early blood-brain barrier (BBB) disruption and astrocytic alterations, whereas the contralateral hippocampus developed a more pronounced and sustained inflammatory response characterized by microglial activation and increased expression of inflammatory and endothelial activation markers. Early intranasal NPY administration attenuated these bilateral pathological alterations by preserving BBB integrity, reducing neuroinflammatory responses, and normalizing glial morphology. These neurobiological effects were accompanied by improvements in spatial working memory and anxiety-related behaviors. Collectively, our findings demonstrate that unilateral TBI induces distinct bilateral secondary injury responses within the hippocampus and identify early intranasal NPY administration as a promising strategy. Further investigation is warranted to clarify the underlying mechanisms and establish the long-term therapeutic potential of NPY.

Keywords:  Anxiety; Astrocytes; Blood-brain barrier; Memory; Microglia; Neuroinflammation; Neuropeptide Y; Traumatic brain injury (TBI)

DOI:  https://doi.org/10.1016/j.bbi.2026.106952
Mov Disord. 2026 Aug 09.

COVID-19 Amplifies Sex-Specific Dopamine and Glial Responses in a Parkinson's Disease Mouse Model.

Ifeoluwa Awogbindin, Mélanie Bourque, Marc Morissette, Marie-Ève Hamelin, Chantal Rhéaume, Jared VanderZwaag, Antonia Landwehr, Disha Patel, Guy Boivin, Marie-Ève Tremblay, Thérèse Di Paolo.

   BACKGROUND: Exposure to environmental agents, including viral infections, may increase Parkinson's disease (PD) susceptibility, especially in males, but the neurodegenerative risk extent of COVID-19 remains uncertain.
OBJECTIVES: We investigated the plausible link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and PD susceptibility across sexes.
METHODS: Mice overexpressing the human angiotensin-converting enzyme 2 receptor (K18-hACE2) were exposed to SARS-CoV-2 or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) doses. This was followed by a two-hit experiment in which mice received a moderate MPTP dose and SARS-CoV-2 11 days post-MPTP. Striatal viral titer was measured 4 days postinfection (dpi). After 14 dpi, striatal dopamine and its metabolites (3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid), nigrostriatal degeneration, and glial responses in males and females were compared.
RESULTS: Only in males, SARS-CoV-2 resulted in progressive dopamine metabolic dysregulation by day 21. Coexposed females showed less weight loss than males. Coexposed males showed significant nigrostriatal degeneration, together with robust nigral astrocytic and microglial reactivity exceeding individual effects. In females, MPTP and/or SARS-CoV-2 had minimal effects on dopamine and its metabolism, degeneration, and microglial reactivity, whereas coexposure was associated with significant nigral astrocytic reactivity. In coexposed males, striatal microglia showed enhanced territorial spacing, whereas in females, they became more clustered, possibly because of an enrichment of cells with larger soma and retracted processes. In males, single or dual exposure stressed degenerating dopamine neurons to shrink and dilate their Golgi bodies, more prominently in the coexposed group.
CONCLUSIONS: This study reports the sex-dependent COVID-19 effects on mice prodromal PD with a differential glial contribution, supporting glial- and sex-based medical approaches. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  COVID‐19; MPTP; Parkinson's disease; SARS‐CoV‐2; astrocytes; dopamine; microglia

DOI:  https://doi.org/10.1002/mds.70454
Aging Cell. 2026 Aug;25(8): e70653

Distinct Transposable Element Transcript Patterns in Microglia Across Aging and Alzheimer's Disease.

Randy A Grant, Rachel L Doser, Thomas J LaRocca.

Microglia, the brain's resident immune cells, are transcriptionally diverse and highly dynamic, but during aging and disease they lose their transcriptomic flexibility and adopt a chronically activated state that is associated with neuroinflammation and pathology. An emerging transcriptomic process that is also increasingly implicated in brain aging, neuroinflammation, and disease is the dysregulation of transposable elements (TEs), repetitive genomic sequences with the potential to cause cellular stress/dysfunction. However, there are limited data on microglial TE transcript patterns in these contexts. Here, we analyzed multiple RNA-seq datasets from isolated human and mouse microglia across aging, Alzheimer's disease (AD), and AD-associated pathology. In contrast to previous observations based on whole-brain tissue and other brain cell types, we found that microglial TE transcript levels remained relatively consistent throughout most of the human lifespan before increasing in late life. We also found that TE transcript levels in microglia from AD patients showed minimal changes compared to age-matched controls, and in RNA-seq analyses of transgenic AD mouse models we observed pathology-associated TE transcript decreases. Subsequent analyses identified inverse associations between TE transcript levels and autophagy/lysosome-related gene expression, and in vitro studies suggested that aging- and AD-relevant stimuli, as well as pharmacological autophagy inhibition, modulate TE transcript expression in cultured human microglia. Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole-brain samples and other cell types in aging and AD.

DOI: https://doi.org/10.1111/acel.70653
Cell Rep. 2026 Aug 10. pii: S2211-1247(26)00873-9. [Epub ahead of print]45(8): 117795

Tgf-β receptor signaling cell-intrinsically controls conserved microglia homeostatic maturation during zebrafish development.

Magali Miserocchi, Pauline De Meyer, Ruben Lattuca, Alice Montanari, Giuliano Ferrero, Giulia Boezio, Didier Y R Stainier, Valérie Wittamer.

  Microglia, embryonically derived tissue-resident macrophages of the central nervous system, are essential for brain development, homeostasis, and disease. Although transforming growth factor β (TGF-β) signaling is required for mammalian microglia ontogeny, its precise role and evolutionary conservation remain unclear. Using zebrafish as a vertebrate in vivo model, we find Tgf-β receptor signaling as a conserved, cell-intrinsic regulator of microglial differentiation. Pharmacological or genetic disruption of Tgf-β receptor function arrests microglial development after progenitor migration to the embryonic neuroepithelium, preventing activation of the microglial gene expression program. Genetic rescue experiments demonstrate a direct requirement for Tgf-β receptor signaling within the myeloid lineage. We identify Tgf-β1 as the key ligand driving this process and show that sustained signaling is required to maintain microglial identity. Adult zebrafish microglia, whose origin differs from that in mice, similarly fail to differentiate without Tgf-β signaling. Together, these findings establish an evolutionarily conserved TGF-β signaling axis that instructs and maintains microglial identity in vivo.

Keywords:  CP: developmental biology; CP: neuroscience; differentiation; hematopoiesis; macrophages; microglia; ontogeny; signaling; transforming growth factor-β; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2026.117795
Cell Rep. 2026 Aug 08. pii: S2211-1247(26)00881-8. [Epub ahead of print]45(8): 117803

APOE3 and APOE4 human astrocytes differentially modulate Alzheimer's disease pathology and microglial responses in chimeric mice.

Joan Cruz-Sese, Marta Mirón-Alcala, María Alfonso-Triguero, Jon Olalde, Leire Ruiz, Nuria Galbis-Gramage, Lorea Cortes, Laura Escobar, Pranav Preman, An Snellinx, Takashi Saito, Takaomi C Saido, Laura Saiz-Aúz, Alberto Rábano-Gutiérrez, Ana M Aransay, Ibai Diez, Julia Tcw, Alison Goate, Bart De Strooper, Elena Alberdi, Amaia M Arranz.

  Astrocytes and APOE are strongly implicated in Alzheimer's disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like astrocytes. APOE3 and APOE4 astrocytes differ in expression of APOE, which associates differentially with Aβ plaques. Notably, APOE3 astrocytes are associated with reduced Aβ burden, Tau pathology, and neuritic dystrophy, whereas APOE4 astrocytes exacerbate these processes. They also induce distinct microglial responses: APOE4 astrocytes enhance microglial clustering around Aβ plaques and promote a disease-associated microglia-like state, whereas APOE3 astrocytes reduce clustering and support a more homeostatic profile. These findings highlight a role for human astrocytes and APOE-dependent astrocyte functions in modulating AD-related pathology.

Keywords:  AD; APOE; Alzheimer's disease; Aβ; CP: neuroscience; CP: stem cell research; amyloid-beta; apolipoprotein E; chimeric mice; hAstrocytes; hiPSCs; human astrocytes; human induced pluripotent stem cells

DOI:  https://doi.org/10.1016/j.celrep.2026.117803
Neurosci Bull. 2026 Aug 08.

An ApoE-Associated Low-Inflammatory Microglial State Emerges After Inflammatory Challenge in Alzheimer's Disease Mice.

Wenwen Cai, Xiaoli Pan, Ting Qian, Shiwen Yu, Ruoqi Zhao, Cuiqing Zhu, Shaoming Sang, Chunjiu Zhong.

  Patients with Alzheimer's disease (AD) frequently experience inflammatory insults; however, the mechanisms by which microglia respond to these challenges remain unclear. Although AD microglia have been proposed to be primed for exaggerated inflammatory responses, single-cell evidence remains limited. To investigate microglial responses to inflammation in AD, we challenged AD mouse models with intraperitoneal lipopolysaccharide (LPS) and used single-cell RNA sequencing to characterize microglial states, along with in vivo immunostaining and in vitro models to define their features and underlying mechanisms. We found that, in response to an inflammatory challenge, microglia adopted a low-inflammatory state accompanied by elevated expression of mitochondrial respiratory chain genes. This state was associated with the phagocytosis of dystrophic neurites and was recapitulated in vitro using an efferocytosis-based model, with apolipoprotein E implicated in its underlying mechanism. In summary, we identified a distinct microglial state that provides new insights into the dynamic role of microglia in AD.

Keywords:  Alzheimer’s disease; Apolipoprotein E; Dystrophic neurites; Microglia priming; Systemic inflammation

DOI:  https://doi.org/10.1007/s12264-026-01693-4
CNS Neurosci Ther. 2026 Aug;32(8): e71073

Cholesterol Drives IFITM3+ Microglia Activation and Induces STING Mediated Neuroinflammation After Ischemic Stroke.

Yue Cheng, Yuxi Zhou, Yonghui Chen, Tianni Shen, Yan Li, Chen Chen, Qiuyue Fan, Jie Qi, Peiying Li, Yueman Zhang.

   AIMS: Cerebral ischemic stroke triggers extensive neuronal membrane breakdown, releasing a massive load of cholesterol that overwhelms resident microglia. Dysregulated microglial cholesterol metabolism has been implicated in post-stroke neuroinflammation, yet the specific pathogenic microglial subpopulations, their molecular signatures, and the downstream inflammatory cascades remain poorly defined.
METHODS: We employed a permanent distal middle cerebral artery occlusion (dMCAO) model combined with single-cell RNA sequencing (scRNA-seq) to profile immune cell transcriptomes and identify cholesterol-associated microglial markers. Cholesterol dynamics, lipid droplet accumulation, and inflammatory marker expression were quantified via immunofluorescence and transmission electron microscopy. Therapeutic interventions included pharmacological cholesterol mobilization with 2-hydroxypropyl-β-cyclodextrin (HβCD), pharmacological STING inhibition with C-176, and microglia-targeted STING knockdown using AAV9 vectors. Cerebral injury and neurological function were assessed through infarct volume measurement, white matter integrity analysis, and behavioral assays (rotarod and grip strength) in dMCAO, tMCAO, and perioperative stroke (PIS) models.
RESULTS: Using scRNA-seq, we identified interferon-induced transmembrane protein 3 (IFITM3) as a specific marker for a microglial subpopulation that was characterized by upregulated ACAT1, enhanced cholesterol esterification, and accumulation of cholesterol crystals and lipid droplets. This IFITM3+ microglia population peaked at 7 days post-stroke and correlated with NLRP3 inflammasome activation and STING signaling. Pharmacological reduction of cholesterol burden with HβCD attenuated lipid droplet formation, suppressed mitochondrial DNA leakage, and inhibited STING pathway activation. Correspondingly, HβCD and C-176 administration significantly reduced cerebral infarct size, mitigated white matter demyelination, and improved motor function in dMCAO and tMCAO models. We further found that AAV-mediated STING knockdown recapitulated the above protective effects in HβCD and C-176 treated stroke mice. Furthermore, HβCD treatment ameliorated microglial inflammation and improved functional outcomes in a PIS model.
CONCLUSION: IFITM3+ microglia is a pro-inflammatory and cholesterol-laden subpopulation that exacerbates post-stroke cerebral ischemic brain injury. Targeting the microglial cholesterol axis by HβCD or inhibiting the STING pathway represents a promising therapeutic strategy to mitigate ischemic brain injury and improve neurological function.

Keywords:  STING; cholesterol; ischemic stroke; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/cns.71073
Oxid Med Cell Longev. 2026 ;2026(1): e9948225

Modelling Ferroptosis in a Human Microglial Line by Sequential Exposure to Iron and GPX4 Inhibition.

Renaud Bussiere, Nikhil Tulsian, Cecilia Wieder, Dewi McConnaughie, Evie Tynan, Andrew Lowe, Esther Cheow, Matthew Choo, Jill C Richardson, James A Duce, Sébastien Gillotin.

  Excessive iron accumulation is a pathological feature of several neurodegenerative diseases (NDDs), and a growing body of evidence suggests that ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, is implicated in their pathogenesis. Microglia, the brain's resident immune cells, buffer iron overload but become susceptible to ferroptotic death, exacerbating neuroinflammation and neuronal loss. To uncover the molecular events leading to microglial ferroptosis, we established a human microglial ferroptosis model using the HMC3 cell line. This model recapitulates core features of ferroptosis, including increased reactive oxygen species (ROS) and peroxidation of lipids at the membrane, both rescued by ferrostatin-1 (Fer-1). We used this model to perform integrated multiomic profiling and identified significant dysregulation in lipid species, notably an accumulation of sterols, including oxysterols such as 7-oxo-cholesterol, alongside the oxidation of polyunsaturated fatty acids (PUFAs) that are characteristic of ferroptosis. Transcriptomic and proteomic analyses corroborate these findings, revealing the upregulation of the mevalonate pathway and cholesterol metabolism. Importantly, the increased expression of some of these key metabolic genes was also reversed by Fer-1 treatment, indicating their role in a preferroptotic signature. Our model provides a novel platform for investigating early molecular events in microglia ferroptosis. Integrating these findings into future investigations could uncover new protective mechanisms against microglial ferroptosis to ensure homeostatic regulation of ROS levels and sterol metabolism.

Keywords:  ferroptosis; lipid metabolism; microglia; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.1155/omcl/9948225
Curr Eye Res. 2026 Aug 11. 1-13

SGLT2i Canagliflozin Exerts Neuroprotection in Diabetic Retinopathy by Inhibiting Microglial Proinflammatory Cytokine Release by Downregulating the TLR4/NF-κB/NLRP3 Pathway.

Tai Guo, Yue Liu, Mengxia He, Yuling Lian, Xiyu Wu, Hanpeng Zhao, Xiaohong Chen, Zhixin Mo, Yuman Li, Mingsi Chi, Xiaofeng Huang, Dejia Fang, Qianli Meng, Shangli Jin, Ning Hou, Ying Cui.

   PURPOSE: Diabetic retinopathy (DR) is the leading cause of preventable blindness among working-age adults. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), first-line treatments for diabetes mellitus (DM), have demonstrated efficacy in decelerating DR progression. However, the mechanisms remain unclear. This study investigates how canagliflozin (CANA), an SGLT2 inhibitor, exerts neuroprotective effects in DR by suppressing microglial proinflammatory cytokine release.
MATERIALS AND METHODS: Using high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice and BV-2 microglial cells under high glucose (HG) conditions, we elucidate the mechanistic link between CANA and neuroinflammation suppression in DR. Retinal structure and function were assessed using optical coherence tomography and electroretinography. Protein was evaluated via Western blotting, immunostaining, and enzyme-linked immunosorbent assay. Cell viability was measured using the Cell Counting Kit-8 assay.
RESULTS: CANA demonstrated significant neuroprotective effects in diabetic retinopathy (DR) by attenuating microglia-mediated neuroinflammation. In HFD and STZ-induced diabetic mice, the ganglion cell complex thickness and a-wave and b-wave amplitudes decreased (p < 0.05). CANA upregulated the ganglion cell complex thickness (p < 0.05) and TSPO expression (p < 0.05), and tended to increase a-wave and b-wave amplitudes (p > 0.05) in retinas in DM mice. In BV-2 cells, HG activated BV-2 cells, downregulated TSPO expression, and promoted proinflammatory cytokine release, toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, and nuclear translocation of p65 and phosphorylated p65 (p < 0.05). CANA reduced BV-2 cell viability, upregulated TSPO, while suppressing proinflammatory cytokine release, TLR4 and NLRP3 expression, and nuclear translocation of p65 and phosphorylated p65 (p < 0.05). Notably, CANA inhibited the TLR4/NF-κB/NLRP3 pathway, evidenced by reduced TLR4/NLRP3 protein levels and diminished nuclear translocation of p65 and phosphorylated p65 in microglia.
CONCLUSIONS: These findings identify CANA as a promising therapeutic candidate for DR, acting through TLR4/NF-κB/NLRP3-dependent modulation of microglial activation.

Keywords:  Sodium-glucose cotransporter 2 inhibitor; canagliflozin; diabetic retinopathy; microglial inflammation; neuroprotection

DOI:  https://doi.org/10.1080/02713683.2026.2714720