bims-microg 2025-06-08 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–06–08
27 papers selected by
Marcus Karlstetter, Universität zu Köln

Intracellular accumulation of amyloid-ß is a marker of selective neuronal vulnerability in Alzheimer's disease.
CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth.
A microglia identity crisis.
Identification of the velum interpositum as a meningeal-CNS route for myeloid cell trafficking into the brain.
4E-BP1-dependent translation in microglia controls mechanical hypersensitivity in male and female mice.
Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice.
HDAC inhibitors engage MITF and the disease-associated microglia signature to enhance amyloid β uptake.
The UNC5C T835M mutation associated with Alzheimer's disease leads to neurodegeneration involving oxidative stress and hippocampal atrophy in aged mice.
Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer's disease.
Ultrabright ratiometric Raman-guided epilepsy surgery by intraoperatively visualizing proinflammatory microglia.
Cell-specific protein expression in Alzheimer's disease prefrontal cortex.
Tau phosphorylation at Alzheimer's disease biomarker sites impairs its cleavage by lysosomal proteases.
Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis.
Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis.
Brd4 expression in CD4 T cells and in microglia promotes neuroinflammation in experimental autoimmune encephalomyelitis.
Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype.
Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus CNS infection.
Modulation of microglial phagocytosis via the GAS6-MERTK pathway regulates pathological angiogenesis in the mouse oxygen-induced retinopathy model.
Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures.
Microglial STING is a central safeguard against neurological decline with age.
Hampered AMPK-ULK1 cascade in Alzheimer's disease (AD) instigates mitochondria dysfunctions and AD-related alterations which are alleviated by metformin.
Reducing degradation of EETs by sEH protein macromolecule depletion prevents MCAO and inhibits microglia-mediated inflammatory response.
Hyaluronan-bisphosphonate conjugate: A macromolecular anti-inflammatory agent and gas delivery system for neuroimmunomodulation in spinal cord injury.
Acetyl-CoA carboxylase activation disrupts iron homeostasis to drive ferroptosis.
Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.
Neutrophil Extracellular Traps Promote AIM2-Dependent Microglial Pyroptosis Following Stroke.
Chronic ozone exposure induces hippocampal microglia activation by microbial dysbiosis in rat lungs.

Nat Commun. 2025 Jun 04. 16(1): 5189

Intracellular accumulation of amyloid-ß is a marker of selective neuronal vulnerability in Alzheimer's disease.

Alessia Caramello, Nurun Fancy, Clotilde Tournerie, Maxine Eklund, Vicky Chau, Emily Adair, Marianna Papageorgopoulou, Nanet Willumsen, Johanna S Jackson, John Hardy, Paul M Matthews.

Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer's disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB+FOXP2+ and L3,5,6 GAD1+FOXP2+ neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB+GPC5+ neurons, which accumulate pTau but not amyloid-β, are not lost even at late Braak stages. We discovered spatial associations between activated microglia and these vulnerable neurons and found that vulnerable RORB+FOXP2+ neuronal transcriptomes are enriched selectively for pathways involved in inflammation and glycosylation and, with progression to AD, also protein degradation. Our results suggest that the accumulation of intraneuronal amyloid-β, which is associated with glial inflammatory pathology, may contribute to the initiation of degeneration of these vulnerable neurons.

DOI: https://doi.org/10.1038/s41467-025-60328-w
Nat Commun. 2025 Jun 03. 16(1): 5145

CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth.

Jiaxin Li, Zhaoyu Wang, Xiaogan Qin, Ming-Chao Zhong, Zhenghai Tang, Jin Qian, Jiayu Dou, Tracy Hussell, Philip D King, Jacques A Nunès, Yuji Yamanashi, Dominique Davidson, André Veillette.

Targeting macrophage inhibitory receptors like signal regulatory protein α (SIRPα) is a promising avenue in cancer treatment. Whereas the ligand of SIRPα, CD47, is widely expressed on tumor cells, its simultaneous presence on all normal cells raises concerns about toxicity and efficacy. This study identifies CD200R1, which binds CD200 on specific tumor types and limited normal cells, as an alternative inhibitory checkpoint for phagocytosis. Blocking or removing CD200R1 from macrophages or CD200 from tumor cells increases phagocytosis and suppresses tumor growth. In humans, CD200R1 is mainly expressed in immunosuppressive macrophages and is induced by interleukin-4. Unlike SIRPα that utilizes phosphatases Src homology 2 domain phosphatase (SHP)-1 and SHP-2, CD200R1 mediates its inhibitory effect via the kinase Csk. Combined CD200R1-CD200 and SIRPα-CD47 blockade further boosts phagocytosis and reduces tumor growth of CD200-expressing tumors, compared to either blockade alone. Thus, targeting CD200R1-CD200 is a promising strategy for immune checkpoint blockade in macrophages, either alone or alongside blockade of other checkpoints.

DOI: https://doi.org/10.1038/s41467-025-60456-3
Neuron. 2025 Jun 04. pii: S0896-6273(25)00355-1. [Epub ahead of print]113(11): 1661-1663

A microglia identity crisis.

Jessie Axsom, F Chris Bennett.

What makes a microglia a microglia? In a recent issue of Cell, Wu et al.1 discover immune cells with microglial gene expression, epigenetic profiles, and ontogeny in the peripheral nervous system of large vertebrates, calling into question long-standing assumptions about microglia identity.

DOI: https://doi.org/10.1016/j.neuron.2025.05.008
Neuron. 2025 May 28. pii: S0896-6273(25)00351-4. [Epub ahead of print]

Identification of the velum interpositum as a meningeal-CNS route for myeloid cell trafficking into the brain.

Lindsay A Hohsfield, Sung Jin Kim, Rocio A Barahona, Caden M Henningfield, Kimiya Mansour, Kristen D Vallejo, Kate I Tsourmas, Nellie E Kwang, Yasamine Ghorbanian, Julio Alejandro Ayala Angulo, Pan Gao, Collin Pachow, Matthew A Inlay, Craig M Walsh, Xiangmin Xu, Thomas E Lane, Kim N Green.

  The borders of the central nervous system (CNS) host a repertoire of immune cells and mediate critical neuroimmune interactions, including the infiltration of peripheral myeloid cells into the CNS. Despite the fundamental role of leukocyte infiltration under physiological and pathological conditions, the neuroanatomical route of cell entry into the brain remains unclear. Here, we describe a specialized structure underneath the hippocampus, the velum interpositum (VI), that serves as a site for myeloid cell entry into the CNS. The VI functions as an extra-parenchymal leptomeningeal extension containing distinct myeloid cells subsets. Fate-mapping studies confirm meningeal and peripheral myeloid cell occupancy within the VI. Additionally, we highlight the distinct use of this route in the developing, irradiated, and demyelinating disease brain, indicating that myeloid cell trafficking through the VI could have important clinical implications for neurological disease.

Keywords:  CSF1R; basement membrane; brain; colony-stimulating factor 1 receptor; demyelinating disease; immune cell trafficking; infiltration; meninges; microglia; myeloid cells; velum interpositum

DOI:  https://doi.org/10.1016/j.neuron.2025.05.004
J Clin Invest. 2025 Jun 02. pii: e180190. [Epub ahead of print]135(11):

4E-BP1-dependent translation in microglia controls mechanical hypersensitivity in male and female mice.

Kevin C Lister, Calvin Wong, Weihua Cai, Sonali Uttam, Patricia Stecum, Rose Rodrigues, Mehdi Hooshmandi, Nicole Brown, Jonathan Fan, Noe Francois-Saint-Cyr, Shannon Tansley, Volodya Hovhannisyan, Diana Tavares-Ferreira, Nikhil Nageshwar Inturi, Khadijah Mazhar, Alain Pacis, Jieyi Yang, Alfredo Ribeiro-da-Silva, Christos G Gkogkas, Theodore J Price, Jeffrey S Mogil, Arkady Khoutorsky.

  Spinal microglia play a pivotal role in the development of neuropathic pain. Peripheral nerve injury induces changes in the transcriptional profile of microglia, including increased expression of components of the translational machinery. Whether microglial protein synthesis is stimulated following nerve injury and has a functional role in mediating pain hypersensitivity is unknown. Here, we show that nascent protein synthesis is upregulated in spinal microglia following peripheral nerve injury in both male and female mice. Stimulating mRNA translation in microglia by selectively ablating the translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) promoted the transition of microglia to a reactive state and induced mechanical hypersensitivity in both sexes, whereas spontaneous pain was increased only in males. Conversely, inhibiting microglial translation by expressing a mutant form of 4E-BP1 in microglia attenuated their activation following peripheral nerve injury and alleviated neuropathic pain in both sexes. Thus, stimulating 4E-BP1-dependent translation promotes microglial reactivity and mechanical hypersensitivity, whereas inhibiting it alleviates neuropathic pain.

Keywords:  Cell biology; Neuroscience; Pain

DOI:  https://doi.org/10.1172/JCI180190
J Clin Invest. 2025 Jun 03. pii: e178349. [Epub ahead of print]

Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice.

Eshu Ruan, Jingpan Lin, Zhao Chen, Qianai Sheng, Laiqiang Chen, Jiating He, Xuezhi Duan, Yiyang Qin, Tingting Xing, Sitong Yang, Mingtian Pan, Xiangyu Guo, Peng Yin, Xiao-Jiang Li, Hong Jiang, Shihua Li, Su Yang.

  Abnormal expansions of CAG trinucleotide repeat within specific gene exons give rise to polyglutamine (polyQ) diseases, a family of inherited disorders characterized by late-onset neurodegeneration. Recently, a new type of polyQ disease was identified and named spinocerebellar ataxia 51 (SCA51). SCA51 is caused by polyQ expansion in THAP11, an essential transcription factor for brain development. The pathogenesis of SCA51, particularly how mutant THAP11 with polyQ expansion contributes to neuropathology, remains elusive. Our study of mouse and monkey brains revealed that THAP11 expression is subject to developmental regulation, showing enrichment in the cerebellum. However, knocking down endogenous THAP11 in adult mice does not affect neuronal survival. In contrast, expressing mutant THAP11 with polyQ expansion leads to pronounced protein aggregation, cerebellar neurodegeneration, and motor deficits, indicating that gain-of-function mechanisms are central to SCA51 pathogenesis. We discovered activated microglia expressing TREM2 in the cerebellum of a newly developed SCA51 knock-in mouse model. Mechanistically, mutant THAP11 enhances the transcription of TREM2, leading to its upregulation. The loss of TREM2 or depletion of microglia mitigates neurodegeneration induced by mutant THAP11. Our study offers the first mechanistic insights into the pathogenesis of SCA51, highlighting the role of TREM2-mediated microglial activation in SCA51 neuropathology.

Keywords:  Genetics; Mouse models; Neurodegeneration; Neuroscience; Protein misfolding

DOI:  https://doi.org/10.1172/JCI178349
Brain Behav Immun. 2025 May 30. pii: S0889-1591(25)00204-1. [Epub ahead of print]

HDAC inhibitors engage MITF and the disease-associated microglia signature to enhance amyloid β uptake.

Verena Haage, John F Tuddenham, Alex Bautista, Frankie Garcia, Charles C White, Ronak Patel, Natacha Comandante-Lou, Victoria Marshe, Jennifer Griffin, Ye Zhou, Deniz Ghaffari, Beatrice Acheson, Mariko Taga, Peter H St George-Hyslop, Rajesh Kumar Soni, Peter A Sims, Vilas Menon, Andrew A Sproul, Philip L De Jager.

  Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes (Keren-Shaul, 2017). Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans (Pettas, 2022; Jauregui, 2023; Friedman, 2018; Mathys, 2019; Tuddenham, 2024); however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate (Butovsky and Weiner, 2018; Wang and Colonna, 2019). Here, we present a pharmacological approach to mimic human DAM in vitro: we validated in silico predictions that two different histone deacetylase (HDAC) inhibitors, Entinostat and Vorinostat, recapitulate aspects of the DAM signature in two human microglia-like model systems. HDAC inhibition increases RNA expression of MITF, a transcription factor previously described as a regulator of the DAM signature (Dolan, 2023). This engagement of MITF appears to be associated with one part of the DAM signature, refining our understanding of the DAM signature as a combination of at least two transcriptional programs that appear to be correlated in vivo. Further, we functionally characterized our DAM-like model system, showing that the upregulation of this transcriptional program by HDAC inhibitors leads to an upregulation of amyloid β and pHrodo Dextran uptake - while E.coli uptake is reduced - and a specific reduction of MCP1 secretion in response to IFN-γ and TNF-α. Overall, our strategy for compound-driven microglial polarization offers potential for exploring the function of human DAM and for an immunomodulatory strategy around HDAC inhibition.

Keywords:  Disease-associated microglia (DAM); Functional analysis; Human microglia; In vitro model systems; Pharmacological modelling

DOI:  https://doi.org/10.1016/j.bbi.2025.05.027
Mol Neurodegener. 2025 Jun 04. 20(1): 65

The UNC5C T835M mutation associated with Alzheimer's disease leads to neurodegeneration involving oxidative stress and hippocampal atrophy in aged mice.

Devi Krishna Priya Karunakaran, Makenna Ley, Joanna Guo, Ammaarah Khatri, Katherine Sadleir, Jelena Popovic, Arun Kumar Upadhyay, Jeffrey Savas, Daniele Procissi, Jasvinder Atwal, Robert Vassar.

Alzheimer's disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and synaptic and neuronal loss. Recently, a rare autosomal dominant coding mutation, T835M, in the Un-coordinated 5c (UNC5C) netrin receptor gene was segregated with late-onset AD (LOAD). Overexpression of T835M in primary hippocampal neurons increased cell death in response to neurotoxic stimuli including beta-amyloid (Aβ) suggesting a mechanism by which T835M may confer increased risk of LOAD. However, the molecular mechanism of T835M-mediated cell death remained under explored. Toward this end, we generated a mouse T835M knock-in (Unc5cKI/KI) model and employed biochemical and histological analyses to understand the molecular mechanism of T835M-mediated pathogenesis in late onset Alzheimer's disease. We show that homozygous KI mice have significantly reduced hippocampal volume, increased ventricular volume, dendritic disorganization (CA1 region) and reduced UNC5C protein level by 12-18 months of age. Further, we show that the neuronal cell death is observed in the Unc5cKI/KI mice by 12 months of age by TUNEL analysis and activated Caspase 3/7 assay. Proteomic analysis of hippocampal samples showed upregulation of oxidative stress and downregulation of chaperone proteins at 18 months corroborating the biochemical and histological results showing increased c-Jun N-terminal Kinase (JNK) phosphorylation, NADPH oxidase, and decreased Netrin1 levels. Moreover, Unc5cKI/KI mice also show morphological changes in the astrocytes with increased number of branched processes, reduced GFAP levels, and significantly increased activation of microglia. Overall, these results suggest that T835M mutation causes neurodegeneration by creating an oxidative stress environment leading to synaptic degeneration and weakened astrocytes, thereby leading to neuronal cell death via apoptosis. Furthermore, to assess the effects of amyloid pathology on the mutation, we crossed Unc5cKI/KI mice with AppNL-G-F/NL-G-F mice and observed an exacerbation of mutation-associated changes along with increased levels of Aβ42, suggesting that the T835M mutation increases the susceptibility of neurons to cell death and elevated Aβ42 levels, thus promoting AD pathogenesis. Understanding the molecular mechanism of cell death in regions susceptible to neurodegeneration such as the hippocampus could shed light on the players and pathways involved in cell death in AD pathogenesis and therefore could inform therapeutic approaches for AD.

DOI: https://doi.org/10.1186/s13024-025-00850-z
Mol Neurodegener. 2025 May 31. 20(1): 62

Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer's disease.

Zhong-Jiang Yan, Maosen Ye, Jiexi Li, Deng-Feng Zhang, Yong-Gang Yao.

   BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and neuroinflammation. The choroid plexus (ChP), serving as the blood-cerebrospinal fluid-brain barrier, plays essential roles in immune response to stress and brain homeostasis. However, the cellular and molecular contributions of the ChP to AD progression remain inadequately understood.
METHODS: To elucidate the molecular abnormalities during the early stages of AD, we acquired single-cell transcription profiling of ChP from APP/PS1 mice with early-stage of Aβ pathology and litter-mate controls. The transcriptional alterations that occurred in each cell type were identified by differentially expressed genes, cell-cell communications and pseudotemporal trajectory analysis. The findings were subsequently validated by a series of in situ and in vitro assays.
RESULTS: We constructed a comprehensive atlas of ChP at single-cell resolution and identified six major cell types and immune subclusters in male mice. The majority of dysregulated genes were found in the epithelial cells of APP/PS1 mice in comparison to wild-type (WT) mice, and most of these genes belonged to down-regulated module involved in mitochondrial respirasome assembly, cilium organization, and barrier integrity. The disruption of the epithelial barrier resulted in the downregulation of macrophage migration inhibitory factor (MIF) secretion in APP/PS1 mice, leading to macrophage activation and increased phagocytosis of Aβ. Concurrently, ligands (e.g., APOE) secreted by macrophages and other ChP cells facilitated the entry of lipids into ependymal cells, leading to lipid accumulation and the activation of microglia in the brain parenchyma in APP/PS1 mice compared to WT controls.
CONCLUSIONS: Taken together, these data profiled early transcriptional and cellular abnormalities of ChP within an AD mouse model, providing novel insights of cerebral vasculature into the pathobiology of AD.

Keywords:  Alzheimer’s disease; Choroid plexus; Lipid accumulation; Neuroinflammation; Single-cell transcriptome

DOI:  https://doi.org/10.1186/s13024-025-00853-w
Cell Rep Med. 2025 May 23. pii: S2666-3791(25)00228-9. [Epub ahead of print] 102155

Ultrabright ratiometric Raman-guided epilepsy surgery by intraoperatively visualizing proinflammatory microglia.

Cong Wang, Zhi Li, Xiao Zhu, Wanbing Sun, Yue Ding, Wenjia Duan, Difei Wang, Yiqing Jiang, Ming Chen, Yuncan Chen, Jiayi Hu, Zheping Cai, Jing Zhao, Junfeng Wang, Zhen Fan, Faming Zheng, Xingyu Zhou, Fang Xie, Jianping Zhang, Yihui Guan, Kui Yan, Zuhai Lei, Qinyue Wang, Luting Wang, Xiao Xiao, Hairong Zheng, Liang Chen, Cong Li, Ying Mao.

  Resective surgery is an effective approach for long-term seizure control in drug-resistant focal epilepsy when the epileptic focus (EF) can be accurately delineated and removed. However, intraoperative mapping of EF with electrocorticography is laborious, time-consuming, and highly vulnerable to the effects of anesthesia. Here, we demonstrated that activated microglia can be reliable biomarkers for EF localization. Leveraging a newly developed ratiometric Raman nanosensor, ultraHOCls, we successfully visualize proinflammatory microglia in live epileptic mice, allowing for precise EF delineation without the interference of anesthesia. Compared to electrocorticography-guided surgery, ultraHOCl-guided surgery results in a substantial 61% reduction in total seizure burden in epileptic mouse models. Notably, ultraHOCls sprayed on freshly excised human brain tissues can effectively discriminate epileptic regions from non-epileptic tissues with high sensitivity (94.89%) and specificity (93.3%). This work provides an alternative strategy for delineating the EF intraoperatively, potentially revolutionizing surgery outcomes in epilepsy patients.

Keywords:  HOCl; Raman imaging; electrocorticography; epilepsy; microglia; myeloperoxidase; ratiometric; surgery

DOI:  https://doi.org/10.1016/j.xcrm.2025.102155
Alzheimers Dement. 2025 Jun;21(6): e70339

Cell-specific protein expression in Alzheimer's disease prefrontal cortex.

Maryam Gholampour, Malay K Basu, Russell H Swerdlow, Xinming Zhuo, Mohammad Haeri.

   INTRODUCTION: Analyzing the proteomes of different brain cell types is fundamental for understanding the pathophysiology of Alzheimer's disease (AD). However, spatial analysis of these diverse and limited cell populations poses significant challenges.
METHODS: The GeoMx Digital Spatial Profiler (DSP) platform was used to analyze protein level in the prefrontal cortex of AD and non-AD brains. The platform interrogated 76 proteins and used immunofluorescence to distinguish between three cell types.
RESULTS: Neprilysin (NEP), which promotes amyloid beta degradation, was significantly higher in AD neurons and microglia. Lysosome-associated membrane protein 2A (LAMP2A) level was higher in neurons of individuals with AD compared to a control group. In addition, markers of neuroinflammation, such as CD11c, CD11b, and CD163, were also elevated in AD neurons.
DISCUSSION: Our findings indicate the DSP platform effectively facilitates cell-specific snapshots of the AD brain proteome.
HIGHLIGHTS: The expression of 76 proteins was studied in neurons, astrocytes, and microglia. We identified 18 differentially expressed proteins in AD neurons. Neprilysin was upregulated in neurons and microglia.

Keywords:  Alzheimer's disease; GeoMx DSP; brain cell types; neprilysin; spatial proteomics

DOI:  https://doi.org/10.1002/alz.70339
Alzheimers Dement. 2025 Jun;21(6): e70320

Tau phosphorylation at Alzheimer's disease biomarker sites impairs its cleavage by lysosomal proteases.

Courtney Lane-Donovan, Andrew W Smith, Rowan Saloner, Bruce L Miller, Kaitlin B Casaletto, Aimee W Kao.

   INTRODUCTION: Phospho-tau peptides from the proline-rich domain (PRD) of tau are sensitive biomarkers for Alzheimer's disease (AD). The PRD is known to be relatively resistant to lysosomal proteolytic cleavage, but the effects of phosphorylation on cleavage are unknown.
METHODS: Using in silico modeling and in vitro protease assays, we quantified the effects of phosphorylation on lysosomal proteolysis of tau. We further assessed levels of lysosomal proteases in patient-derived cerebrospinal fluid (CSF) relative to phosphorylated tau-181 (p-tau181).
RESULTS: Phosphorylation renders the PRD significantly resistant to cleavage by the lysosome, especially at less acidic pH setpoints. In Alzheimer's disease subjects, CSF levels of lysosomal proteases correlate with p-tau181, suggesting that p-tau peptides are released with lysosomal contents.
DISCUSSION: Loss of lysosomal acidity may contribute to the release of phospho-tau biomarkers. This study shows that phosphorylation of tau impairs its cleavage by proteases in a pH-dependent manner and provides a novel molecular basis for p-tau biomarker accumulation in AD.
HIGHLIGHTS: Phosphorylated tau-181 (p-tau181) and p-tau217 originate from tau regions that are poorly cleaved by lysosomal proteases. Phosphorylation further impairs the proteolytic cleavage of AD biomarker peptides. Impaired proteolytic cleavage of phosphorylated tau is pH dependent. Levels of p-tau181 are correlated with lysosomal proteases in Alzheimer's disease (AD) cerebrospinal fluid samples. AD-associated lysosomal dysfunction may contribute to presence of disease biomarkers.

Keywords:  Alzheimer's disease; biomarker; lysosome; neurodegeneration; phosphorylated tau; protease

DOI:  https://doi.org/10.1002/alz.70320
Acta Neuropathol. 2025 Jun 02. 149(1): 55

Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis.

Fan Liao, Maria Calvo-Rodriguez, Meha Chhaya, Julian P Sefrin, Erik I Charych, Mario Mezler, Diana Clausznitzer, Emily J McGlame, Karen Zhao, Allison Rodgers, Yang Cao, Philipp F Secker, Laura Fernandez Garcia-Agudo, Lili Huang, Corinna Klein, Tammy Dellovade, Eric Karran.

  Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (AβpE3). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant AβpE3-42 fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. In vivo two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.

Keywords:  Alzheimer’s Disease; Amyloid; Microglia; Passive immunotherapy; Two-photon microscopy

DOI:  https://doi.org/10.1007/s00401-025-02892-5
Transl Neurodegener. 2025 Jun 04. 14(1): 29

Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis.

Ling Lei, Yilei Cheng, Anqi Yin, Jian-Min Han, Gang Wu, Fumin Yang, Qi Wang, Jian-Zhi Wang, Rong Liu, Hong-Lian Li, Xiaochuan Wang.

   BACKGROUND: Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for > 95% of all Alzheimer's disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD. However, the mechanisms underlying the susceptibility of the Hippo-YAP1 signaling pathway in the context of LOAD remain unclear.
METHODS: AAV9-YAP1-RNAi was injected into the hippocampi of C57BL/6J mice to establish a YAP1 knockdown model. Overexpression of full-length YAP1 was achieved by injecting AAV9-YAP1 into the hippocampi of SAMP8 mice. To establish the model of knockdown of nuclear receptor subfamily 4 group A member 1 (Nr4a1), AAV9-Nr4a1-RNAi was injected into the hippocampi of SAMP8 mice. In the C57BL/6J mice with YAP1 knockdown, Nr4a1 expression was either knocked down or inhibited with DIM-C to examine the impact of Nr4a1 on tau phosphorylation and cognitive deficits. Primary hippocampal neurons from Sprague-Dawley (SD) rats were infected with lentivirus (LV)-YAP1 to create a YAP1 overexpression model, and Aβ treatment was used to induce neuronal senescence. Protein levels were assessed using immunofluorescence, Western blotting, and ELISA. Animal behavior was evaluated using the Morris water maze test, novel object recognition test, and open field test.
RESULTS: YAP1 was reduced in the hippocampus of both aged C57BL/6J mice and SAMP8 AD model mice through Hippo pathway activation, as well as in Aβ-induced senescent neurons. Overexpression of YAP1 in primary neurons significantly mitigated the Aβ-induced neuronal senescence by downregulating several senescence-related genes, including p16 and p53. The levels of phosphorylated AKT/GSK-3β in neurons were increased with overexpression of YAP1 both in vivo and in vitro. Knockdown of YAP1 induced AD-like symptoms and exacerbated cognitive decline in 2-month-old C57BL/6J mice. Injection of AAV9-YAP1 in the brains of SAMP8 mice partially alleviated neuronal senescence and enhanced cognitive function. Notably, genetic knockdown and chemical inhibition of Nr4a1 significantly ameliorated cognitive deficits as well as AD-like pathology in these subjects.
CONCLUSIONS: These findings reveal an etiopathogenic relationship between aging and AD, which is associated with the YAP1-Nr4a1-AKT/GSK-3β signaling pathway. Our findings provide insight into the therapeutic strategies aimed at delaying brain aging and combating neurodegenerative diseases such as AD.

Keywords:  Alzheimer’s disease; Nr4a1; Senescence; YAP1

DOI:  https://doi.org/10.1186/s40035-025-00487-4
J Neuroinflammation. 2025 Jun 02. 22(1): 148

Brd4 expression in CD4 T cells and in microglia promotes neuroinflammation in experimental autoimmune encephalomyelitis.

Anup Dey, Matthew Butcher, Anne Gegonne, Ryoji Yagi, Keita Saeki, Eunju Lee, Dinah S Singer, Jinfang Zhu, Keiko Ozato.

  Microglia are resident innate immune cells in the central nervous system (CNS) that provides anti-microbial protection but also promote neuroinflammation. BRD4 is a chromatin reader that binds to acetylated histones and directs transcription of numerous genes. However, it is unknown whether and how BRD4 regulates microglia function. We addressed the role of microglia and BRD4 in a neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. It was reported earlier that in EAE, upon initial T cell activation in the peripheral lymphoid organs, CD4+ T cells migrate to CNS and are reactivated by resident or migratory antigen presenting cells resulting in full manifestation of EAE (Rossi and Constantin, Front Immunol 7:506, 2016), (Plastini et al., Front Cell Neurosci 14:269, 2020). Using conditional deletion of Brd4 in CD4 T cells, we reveal that BRD4 regulates T helper cell differentiation and promotes T cell migration to CNS resulting in EAE. It remained unclear whether resident microglia are capable of reactivating migrating T cells to the CNS and if BRD4 plays a role in the process. To determine the role of microglial BRD4 in EAE, we constructed conditional knockout mice lacking Brd4 (Brd4cKO) in microglia. RNA-seq analysis showed that Brd4 deletion led to the downregulation of many microglia genes in both naive and EAE conditions. Consequently, Brd4cKO mice had markedly reduced EAE pathology, namely reduced paralysis, absence of axonal demyelination and inhibited expression of inflammatory cytokines. In vehicle treated mice (vehicle) abundant number of T cells were found to be near microglia that may lead to T cell- microglia interaction and T cell reactivation. In contrast, the number of T cells detected in the CNS of Brd4cKO mice was much fewer. This may lead to reduced T cell- microglia interaction, failure of T cells to get reactivated and hence failed to achieve full manifestation of EAE. These results demonstrate that microglia are critically involved in EAE disease progression for which BRD4 is essential. In summary, BRD4 directs transcription of genes defining microglia function. By so doing BRD4 promotes demyelination and neuroinflammation to exacerbate EAE.

Keywords:  BRD4; Brd4cKO; CNS; EAE; MOG; Microglia; Neuroinflammation; RNA-seq; Th17 T cells

DOI:  https://doi.org/10.1186/s12974-025-03449-9
J Neuroinflammation. 2025 Jun 02. 22(1): 147

Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype.

Marianna Hellén, Isabelle Weert, Stephan A Müller, Noora Räsänen, Pinja Kettunen, Šárka Lehtonen, Michael Peitz, Klaus Fließbach, Mari Takalo, Marja Koskuvi, Stefan F Lichtenthaler, Ville Leinonen, Alfredo Ramirez, Olli Kärkkäinen, Mikko Hiltunen, Jari Koistinaho, Taisia Rõlova.

   BACKGROUND: The ε4 isoform of apolipoprotein E (ApoE) is the most significant genetic risk factor for Alzheimer's disease. Glial cells are the main source of ApoE in the brain, and in microglia, the ε4 isoform of ApoE has been shown to impair mitochondrial metabolism and the uptake of lipids and Aβ42. However, whether the ε4 isoform alters autophagy or lysosomal activity in microglia in basal and inflammatory conditions is unknown.
METHODS: Altogether, microglia-like cells (iMGs) from eight APOE3/3 and six APOE4/4 human induced pluripotent stem cell (iPSC) lines were used in this study. The responses of iMGs to Aβ42, LPS and IFNγ were studied by metabolomics, proteomics, and functional assays.
RESULTS: Here, we demonstrate that iMGs with the APOE4/4 genotype exhibit reduced basal pinocytosis levels compared to APOE3/3 iMGs. Inflammatory stimulation with a combination of LPS and IFNγ or Aβ42 induced PI3K/AKT/mTORC signaling pathway, increased pinocytosis, and blocked autophagic flux, leading to the accumulation of sequestosome 1 (p62) in both APOE4/4 and APOE3/3 iMGs. Exposure to Aβ42 furthermore caused lysosomal membrane permeabilization, which was significantly stronger in APOE4/4 iMGs and positively correlated with the secretion of the proinflammatory chemokine IL-8. Metabolomics analysis indicated a dysregulation in amino acid metabolism, primarily L-glutamine, in APOE4/4 iMGs.
CONCLUSIONS: Overall, our results suggest that inflammation-induced metabolic reprogramming places lysosomes under substantial stress. Lysosomal stress is more detrimental in APOE4/4 microglia, which exhibit endo-lysosomal defects.

Keywords:  Alzheimer’s disease; Apolipoprotein E; Lysosomal dysfunction; Microglia; iPSC

DOI:  https://doi.org/10.1186/s12974-025-03470-y
J Neuroinflammation. 2025 May 31. 22(1): 146

Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus CNS infection.

Xiangning Ding, Xin Lai, Ida H Klaestrup, Sara R N Jensen, Morten M Nielsen, Kasper Thorsen, Marina Romero-Ramos, Yonglun Luo, Lin Lin, Line S Reinert, Søren R Paludan.

   BACKGROUND: Herpes Simplex Virus 1 (HSV-1) is a neurotropic virus causing encephalitis and post-infectious complications. Infections can induce a range of acute, subacute, and progressing brain disease, and in recent years it has emerged that immune responses are involved in the pathogenesis of these diseases.
METHODS: Mice were infected with HSV-1 through corneal infection, and the brain stem was analyzed using single-cell and GeoMx spatial transcriptomics. Through these technologies we profiled temporal transcriptomic changes in cell populations, pathways, and cell-cell communication associated with antiviral activity and inflammation-induced disturbance of physiological brain structures and activities.
RESULTS: We found that microglia proportions increased early after HSV-1 infection, followed by monocyte influx and later by T cells. The blood-brain barrier was disrupted, and transcriptomic profiles associated with homeostatic brain transcriptional activities were altered. Early transcriptional responses were dominated by antiviral and inflammatory activities. A microglia subpopulation with high type I interferon and chemokine expression localized to infection sites, likely mediating antiviral defense and immune recruitment. Monocyte subpopulations displayed a broader activation profile than microglia and was a central mediator of crosstalk between immune cells. Cytokines from microglia, monocytes, and T cells reprogrammed brain cells, notably endothelial cells and oligodendrocytes, disrupting brain functions. Comparing datasets from various brain diseases revealed the identified microglia subpopulation as specific to viral infections.
CONCLUSIONS: This study identifies a unique population of virus-activated microglia with antiviral and proinflammatory properties and reveals monocytes to be a key driver of interactions driving pathology in the virus-infected brain.

Keywords:  Infection-induced brain inflammation; Single-cell RNA sequencing; Viral brain infection

DOI:  https://doi.org/10.1186/s12974-025-03471-x
Cell Death Dis. 2025 Jun 02. 16(1): 428

Modulation of microglial phagocytosis via the GAS6-MERTK pathway regulates pathological angiogenesis in the mouse oxygen-induced retinopathy model.

Canelif Yilmaz, Irina Korovina, Anke Witt, Farid Abdallah, Bianca Müller, Carmen Hentsche, Anika Fleischhauer, Stephan Speier, Andreas Deussen, Anne Klotzsche-von Ameln.

Ischemic retinopathies (IR) are major causes of blindness worldwide. They are characterized by an exuberant hypoxia-driven pathological neovascularization (NV). While it is well accepted that immune cells contribute to both physiological and pathological retinal angiogenesis, our knowledge of various processes and underlying mechanisms, especially in the direct interaction with endothelial cells (EC), is still very limited. Here, we addressed the role of microglial phagocytosis of apoptotic EC in the context of pathological hypoxia-related NV in the mouse oxygen-induced retinopathy model (OIR). We utilized endothelium-specific fluorescent reporter mice to study the kinetics of EC phagocytosis by leukocytes in OIR. Indeed, we observed phagocytic microglia in close proximity to the pathological vessels and an altered phagocytosis rate by flow cytometry compared to controls. We observed a decrease in the phagocytic rate in early hypoxia-driven stages of OIR, whereas in later stages where pathological vessels appear, the phagocytosis rate was increased. Myeloid-specific deletion of the suppressor of cytokine signaling protein 3 (SOCS3) was previously shown to induce increased phagocytic activity due to overexpression of the opsonin molecule growth arrest-specific 6 (GAS6). In myeloid SOCS3-deficient mice, we observed a reduction of pathological NV in OIR. This reduction could be reversed by neutralizing GAS6 via administration of recombinant MERTK protein, the receptor for GAS6 expressed on myeloid cells. Furthermore, exogenous GAS6 supplementation increased microglial phagocytosis in vitro and limited pathological NV in OIR. Our data suggest that the promotion of immune cell phagocytosis by the modulation of the GAS6-MERTK axis might represent a potential target for the treatment of pathological NV in IR.

DOI: https://doi.org/10.1038/s41419-025-07744-4
Cell Rep. 2025 Jun 03. pii: S2211-1247(25)00548-0. [Epub ahead of print]44(6): 115777

Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures.

Alexandra M Lish, Nancy Ashour, Richard V Pearse, Paige C Galle, Gwendolyn A Orme, Sarah E Heuer, Courtney R Benoit, Kellianne D Alexander, Elyssa F L Grogan, Gizem Terzioglu, Allegra Scarpa, Andrew M Stern, Nicholas Seyfried, Vilas Menon, Tracy L Young-Pearse.

  Advancements in human induced pluripotent stem cell (hiPSC) technology have enabled co-culture models for disease modeling in physiologically relevant systems. However, co-culturing protocols face challenges in usability and consistency. Here, we introduce a robust, reproducible hiPSC-derived co-culture system integrating astrocytes, neurons, and microglia. This model leverages cryopreserved cells, enabling co-cultures within 20 days post-thaw. Comparing monocultures and tricultures, we demonstrate how cell-cell interactions shape transcriptional and functional states across all three cell types. Neurons in triculture exhibit increased spine density and activity, while astrocytes and microglia show altered responses to proinflammatory stimulation. Surprisingly, the presence of astrocytes induces upregulation of disease-associated microglia (DAM) genes, including TREM2, SPP1, APOE, and GPNMB in microglia. Additionally, while familial Alzheimer's disease neurons induce a prototypical inflammatory response in microglia, the DAM signature is significantly dampened. Collectively, this study establishes a versatile human triculture model as a valuable resource for dissecting neuron-glia interactions and their role in neurodegenerative disease.

Keywords:  APOE; Alzheimer’s disease; CP: Neuroscience; CP: Stem cell research; TREM2; astrocytes; disease-associated microglia; fAD; iPSCs; microglial states; triculture

DOI:  https://doi.org/10.1016/j.celrep.2025.115777
Cell Rep. 2025 May 30. pii: S2211-1247(25)00520-0. [Epub ahead of print]44(6): 115749

Microglial STING is a central safeguard against neurological decline with age.

Katherine B Sulka, Kimberly A Carroll, Machlan Sawden, Jacob W Hopkins, Sasha A Smolgovsky, Abraham L Bayer, Eric Reed, Albert Tai, Pilar Alcaide, Philip Haydon, Shruti Sharma.

  Functional decline of the central nervous system (CNS) is driven by the breakdown of the blood-brain barrier (BBB) and attendant inflammation, all hallmarks of age-related neurodegeneration. Despite intense interest in how the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway impacts neurodegenerative processes in aging, its role in shaping these features of CNS fate during physiological aging remains unclear. Here, using physiologically aged mice, we uncovered an unexpected but vital role for STING in preserving CNS function. We find that STING deficiency exacerbates neurological decline through BBB breakdown, microhemorrhages, and neuromotor deficits. Furthermore, STING deficiency leads to an accrual of neuronal DNA damage and alters CNS proinflammatory, type I interferon, and senescence signatures. Cumulatively, these changes lead to a transformation in microglia phenotypes and transcriptomes. Finally, microglial-STING expression is sufficient to elicit protection against age-associated changes in the CNS and highlights the mechanistic basis for STING-dependent protective mechanisms within the aging brain.

Keywords:  CNS; CP: Immunology; CP: Neuroscience; DNA damage; STING; aging; blood-brain barrier; inflammation; innate immunity; microglia; neuro-motor dysfunction; senescence; type 1 interferons

DOI:  https://doi.org/10.1016/j.celrep.2025.115749
Alzheimers Res Ther. 2025 Jun 02. 17(1): 127

Hampered AMPK-ULK1 cascade in Alzheimer's disease (AD) instigates mitochondria dysfunctions and AD-related alterations which are alleviated by metformin.

Arnaud Mary, Samantha Barale, Fanny Eysert, Audrey Valverde, Sandra Lacas-Gervais, Charlotte Bauer, Sabiha Eddarkaoui, Luc Buée, Valérie Buée-Scherrer, Frédéric Checler, Mounia Chami.

  The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key cellular signaling node, the alteration of which likely contribute to AD development. This study investigated the AMPK-ULK1 pathway activation state in AD and the impact of its modulation on mitochondria structure and function as well as on AD-related alterations. We show in human sporadic AD and 3xTgAD mice brains a defective activating phosphorylation of ULK1 despite the active phosphorylation of AMPK. In addition, we reported defective p-AMPK and p-ULK1 in cells expressing the amyloid precursor protein with the familial Swedish mutation. We then show that the antidiabetic metformin (Met) drug-mediated AMPK-ULK1 cascade activation alleviates structural and functional mitochondrial abnormalities in AD cells and mice brains. Furthermore, in the 3xTgAD brains, it reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as amyloid beta (Aβ) burden, microgliosis and astrogliosis occurring at a later disease stage. AMPK-ULK1 activation increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments and the recruitment of Iba1+ cells to Aβ plaques in vivo and enhances cathepsin D activity and phagocytic activity of microglia in vitro. Additionally, AMPK-ULK1 activation normalizes dendritic spine morphology in organotypic hippocampal slice cultures modeling AD and alleviates learning deficit in symptomatic 3xTgAD mice. Our study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.

Keywords:  AD mice model; AMPK; APP; APP-CTFs; Alzheimer’s disease; Aβ; Inflammation; Mitochondria; ULK1

DOI:  https://doi.org/10.1186/s13195-025-01772-0
Int J Biol Macromol. 2025 May 30. pii: S0141-8130(25)05372-3. [Epub ahead of print]317(Pt 1): 144820

Reducing degradation of EETs by sEH protein macromolecule depletion prevents MCAO and inhibits microglia-mediated inflammatory response.

Jing Xu, Hong Guan, Lixi Bai, Zhichao Xu, Junkai Du.

  Endogenous endorphin (EETs) accumulation plays a neuroprotective role after cerebral ischemia-reperfusion injury, but the regulatory mechanism of its degradation remains unclear. With the deepening understanding of the role of sEH proteinin the metabolism of EETs, it has been suggested that depletion of sEH protein (encoded by EPHX2 gene) macromolecules may reduce the degradation of EETs, which is of great significance for improving cerebral ischemic injury. In this paper, we used CRISPR/Cas9 technique to construct EPHX2 gene knockout rat model and evaluate its role in MCAO. Primary microglia were isolated and transfected, cell viability analysis, ELISA, qPCR and immunohistochemistry were performed to systematically evaluate the effects of sEH on EETs degradation, neural function and inflammatory response. It was found that sEH depletion significantly alleviated the pathological changes and reduced the degradation of EETs in MCAO rats. Antagonistic EETs could reverse the neuroprotective effects of sEH depletion. Further analysis showed that sEH depletion inhibited the inflammatory response by regulating the phenotypic transition of microglia. Specific mechanisms include inhibition of IFN-γ-induced microglial inflammatory responses via EETs and inhibition of p-p38/NF-κB signaling pathways. Studies have revealed that sEH protein is a key regulator of EETs degradation, and sEH protein macromolecule depletion can effectively reduce the metabolic degradation of EETs, thereby alleviating cerebral ischemic injury and relieving inflammation.

Keywords:  Inflammatory response; MCAO; Microglia-mediated; Reduce EETs degradation; sEH protein macromolecule

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144820
Int J Biol Macromol. 2025 Jun 03. pii: S0141-8130(25)05511-4. [Epub ahead of print] 144958

Hyaluronan-bisphosphonate conjugate: A macromolecular anti-inflammatory agent and gas delivery system for neuroimmunomodulation in spinal cord injury.

Ranxi Chen, Hexu Zhang, Shan Pei, Ya Li, Zhiyan Wu, Chaoyong He, Runxiang Yao, Lili Wang, Tantai Zhao, Liyang Shi.

  Neuroinflammation-mediated secondary injury following spinal cord injury (SCI) significantly exacerbates neuronal damage and impedes neurofunctional recovery. Hyaluronan-bisphosphonate (HA-BP) conjugates have emerged as a promising therapeutic agent with selective anti-inflammatory properties in bone and cartilage disorders, yet its potential in SCI remains unexplored. In this study, we highlight the unique role of HA-BP conjugates in modulating neuroinflammation. Our results show that HA-BP conjugates effectively reduce LPS-induced pro-inflammatory activation of microglia and macrophages. Additionally, we developed an HA-BP-based macromolecular hydrogel via metal-ligand coordination, serving as a platform for therapeutic gas delivery. Cellular and animal studies demonstrated that HA-BP-based hydrogels without gas-releasing properties could suppress pro-inflammatory responses, while HA-BP hydrogels with gas-releasing capabilities not only further reduced reduced pro-inflammatory marker (iNOS) but also enhanced anti-inflammatory marker (CD206) expression. In a rat SCI model, the gas-releasing HA-BP hydrogel significantly reduced glial scar formation, promoted regeneration and survival of neurofilament- and class III β-tubulin-positive neurons, and improved motor functional recovery. This study underscores the therapeutic potential of HA-BP conjugates in neuroimmunomodulation, introducing a new application of HA-BP as both an anti-inflammatory agent and a gas-delivery platform for SCI treatment.

Keywords:  Anti-inflammatory macromolecules; Gas-releasing platform; HA-BP conjugate; Neuroimmunomodulation; Spinal cord injury

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144958
Free Radic Biol Med. 2025 May 29. pii: S0891-5849(25)00720-8. [Epub ahead of print]237 110-130

Acetyl-CoA carboxylase activation disrupts iron homeostasis to drive ferroptosis.

Ziqi Han, Shuangyu Han, Xiaoyan Fang, Mengyu Lu, Yuanling Mao, Leilei Shi, Junxiu Song, Tian Wang, Jichen Xiao, Li Xiang, Changqing Yang, Zhigang Zhu, Yubao Wang, Jing Feng.

  Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in de novo lipogenesis. Here, we show a unique function of ACC in disrupting cellular iron homeostasis to drive ferroptosis, an iron-dependent, lipid peroxidation-induced form of cell death. We observed neuronal lipid accumulation and elevated labile iron pool associated with ACC dephosphorylation in mouse models of obstructive sleep apnea (OSA), a highly prevalent neurodegenerative disorder. ACC gene (Acaca) knockout (KO) or inhibition of its enzymatic activity rescued cellular iron metabolism through restoring lysosomal integrity and function, suppressing neuronal ferroptosis. ACC inactivation-driven lysosomal iron homeostasis requires the NFE2L2/NRF2-TFEB axis. Empagliflozin mitigates cellular iron overload via the ACC-NRF2-TFEB-lysosome pathway to alleviate neuronal ferroptosis, cognitive impairment, and mood dysfunction in OSA mice. Furthermore, inhibiting neuronal ACC reduces microglial activation, characterized by elevated complement proteins and pro-inflammatory cytokines, while microglia-specific C1qa KO prevents neuronal injury in OSA mice. Our findings identify a unique coupling between iron homeostasis and lipogenic signaling, suggesting ACC as a potential therapeutic target for neuronal ferroptosis and the resultant microgliosis in neurodegenerative diseases.

Keywords:  Acetyl-CoA carboxylase; Cognitive impairment; Ferroptosis; Iron homeostasis; Lysosome

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.421
Fluids Barriers CNS. 2025 Jun 03. 22(1): 55

Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.

Adnan Akif, Thi Thanh My Nguyen, Langni Liu, Xiaotian Xu, Amol Kulkarni, Jianxiong Jiang, Yang Zhang, Jiukuan Hao.

   BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.
METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.
RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.
CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  Inflammasome; Inflammation; Ischemia; NLRP3; Vascular dementia

DOI:  https://doi.org/10.1186/s12987-025-00665-6
Aging Dis. 2025 Jun 02.

Neutrophil Extracellular Traps Promote AIM2-Dependent Microglial Pyroptosis Following Stroke.

Hanze Chen, Linhui Ni, Jinhua Zhang, Xu Zheng, Yigang Chen, Xing Jin, Beibei Hu, Xinxin Xu, Qiwen Tang, Shuang Li, Yonggang Hao, Shilong Sun, Chengbin He, Shuxia Cao, Xingyue Hu.

Neutrophils are among the earliest and most abundant immune cells infiltrating the brain following ischemic stroke, aggravating neuroinflammation through the formation of neutrophil extracellular traps (NETs). Pyroptosis, an inflammasome-mediated form of programmed cell death, occurs in post-stroke brain tissue and amplifies inflammation by releasing proinflammatory mediators, propagating the inflammatory cascade. However, the mechanistic link between NETs and pyroptosis remains unclear. This study demonstrated significantly elevated NET levels in arterial blood at the infarct site compared with venous or femoral arterial blood in stroke patients. A positive correlation was observed between the 24-h change in NIHSS score (NIHSSbaseline - NIHSS24h) and the difference in arterial citrullinated histone 3 (CitH3)-DNA (NETs) levels between the infarct site and femoral artery (NETsinfarct site - NETsfemoral artery). In a murine stroke model, NETs were detected in the brain parenchyma. Pharmacological inhibition of NET formation with GSK484, a selective protein-arginine deiminase type 4 antagonist, suppressed NET production, reduced absent in melanoma 2 (AIM2) inflammasome expression, and improved neurological outcomes in mice following stroke. AIM2 knockdown in brain tissue achieved similar neuroprotective effects. In both BV2 cells and stroke-induced mice, NETs triggered AIM2-dependent pyroptosis. These findings suggest that neutrophils in peripheral blood infiltrate the brain parenchyma to generate NETs, activating the AIM2 inflammasome in microglia and exacerbating stroke-induced brain injury through pyroptosis. Targeting NET formation or AIM2 inflammasome activation represents a potential therapeutic strategy for attenuating post-stroke neuroinflammation and secondary neuronal damage.

DOI: https://doi.org/10.14336/AD.2024.1733
Ecotoxicol Environ Saf. 2025 Jun 03. pii: S0147-6513(25)00729-8. [Epub ahead of print]300 118393

Chronic ozone exposure induces hippocampal microglia activation by microbial dysbiosis in rat lungs.

Qiuyu Yang, Xueshan Cao, Shanshan Li, Xiaoqi Yang, Pengyu Bai, Yuandong Yan, Changcun Qi, Zhaorui Deng, Bailin Wu, Bo Song.

  Ozone (O3) pollution has become a significant international public health issue with adverse effects on human health. Recent studies have confirmed that O3 exposure induces neuroinflammation and cognitive dysfunction. It is hypothesized that O3 exposure affects the pulmonary microbiome, triggering inflammatory responses that subsequently contribute to neuroinflammation. After 40 days of O3 exposure in rats, distinct changes in the microbial community were identified using 16S rRNA gene sequencing. This was followed by an assessment of the impact of pulmonary microbiota on serum NETs (neutrophil extracellular traps). Additionally, changes in the hippocampal P2X4R/NLRP3 signaling pathway were investigated following O3 exposure. In vitro experiments were conducted to evaluate the effects of O3 on BV-2 cells. In vivo results indicated that O3 exposure led to an increased abundance of Pseudomonas aeruginosa within the pulmonary microbiota and significantly increased NET levels in rat serum. O3 exposure caused a loose arrangement of hippocampal neurons in rats, resulting in cell atrophy and even death. Compared to controls, O3 exposure significantly upregulated the expression of P2X4R/NLRP3 and pro-inflammatory factors. Similarly, BV-2 cells treated with serum from 1.0 ppm O3-exposed rats exhibited comparable changes. Treatment with a P2X4R inhibitor significantly reduced pathway protein and pro-inflammatory factors expression compared to O3 serum intervention alone. In conclusion, O3 exposure significantly alters the pulmonary microbiome, induces hippocampal damage, and NETs may act as a mediator between the lung and brain axes.

Keywords:  Microglia; Ozone; P2X4R/NLRP3 pathway; PA; Pulmonary microbiome

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118393