bims-microg 2025-04-20 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–04–20
sixteen papers selected by
Marcus Karlstetter, Universität zu Köln

Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins.
The "don't eat me" signal CD47 is associated with microglial phagocytosis defects and autism-like behaviors in 16p11.2 deletion mice.
Microglial Lcn2 knockout enhances chronic intracerebral hemorrhage recovery by restoring myelin and reducing inflammation.
Cannabinoid CB2 receptor controls chronic itch by regulating spinal microglial activation and synaptic transmission.
Divergent neurodegeneration associations with choroid plexus volume and degree of calcification in cognitively normal APOE ε4 carriers and non-carriers.
Synergistic reduction in interfacial flexibility of TREM2R47H and ApoE4 may underlie AD pathology.
Sex-specific regulation of microglial MyD88 in HMGB1-Induced anxiety phenotype in mice.
Monocyte-secreted Wnt reduces the efficiency of central nervous system remyelination.
Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis.
μGlia-Flow, an automatic workﬂow for microglia segmentation and classification.
A new nano-encapsulated TSPO ligand reduces neuroinflammation and improves cognitive functions in Alzheimer's disease model.
Sex differences in brain iron deposition and microglial ferritin in Alzheimer's disease.
Evaluation of the Anti-Inflammatory Effects of Novel Fatty Acid-Binding Protein 4 Inhibitors in Microglia.
Menopause triggers microglia-associated neuroinflammation in Parkinson's disease.
Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors.
Depletion of HSP60 in Microglia Leads to Synaptic Dysfunction and Depression-Like Behaviors Through Enhanced Synaptic Pruning in Male Mice.

Cell Stem Cell. 2025 Apr 09. pii: S1934-5909(25)00099-2. [Epub ahead of print]

Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins.

Jean Paul Chadarevian, Hayk Davtyan, Alina L Chadarevian, Jasmine Nguyen, Joia K Capocchi, Lauren Le, Adrian Escobar, Talar Chadarevian, Kimiya Mansour, Ekaterina Deynega, Michael Mgerian, Christina Tu, Sepideh Kiani Shabestari, William Carlen-Jones, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Robert C Spitale, Mathew Blurton-Jones.

  Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer's disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.

Keywords:  Alzheimer’s disease; CRISPR; iMG; iPSC; immune cell therapy; microglia; microglia replacement; neprilysin; neurodegeneration; payload delivery

DOI:  https://doi.org/10.1016/j.stem.2025.03.009
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2411080122

The "don't eat me" signal CD47 is associated with microglial phagocytosis defects and autism-like behaviors in 16p11.2 deletion mice.

Jun Ju, Yifan Pan, Xinyi Yang, Xuanyi Li, Jinghong Chen, Shiyu Wu, Sheng-Tao Hou.

  Various pathological characteristics of autism spectrum disorder (ASD) stem from abnormalities in brain resident immune cells, specifically microglia, to prune unnecessary synapses or neural connections during early development. Animal models of ASD exhibit an abundance of synapses in different brain regions, which is strongly linked to the appearance of ASD behaviors. Overexpression of CD47 on neurons acts as a "don't eat me" signal, safeguarding synapses from inappropriate pruning by microglia. Indeed, CD47 overexpression occurs in 16p11.2 deletion carriers, causing decreased synaptic phagocytosis and the manifestation of ASD characteristics. However, the role of CD47 in synaptic pruning impairment leading to ASD phenotypes in the 16p11.2 deletion mouse model is unclear. Moreover, whether blocking CD47 can alleviate ASD mice's behavioral deficits remains unknown. Here, we demonstrate a strong link between increased CD47 expression, decreased microglia phagocytosis capacity, and increased impairment in social novelty preference in the 16p11.2 deletion mice. The reduction in microglia phagocytosis caused a rise in excitatory synapses and transmission in the prefrontal cortex of 16p11.2 deletion mice. Importantly, blocking CD47 using a specific CD47 antibody or reducing CD47 expression using a specific short hairpin RNA (shRNA) enhanced the microglia phagocytosis and reduced excitatory transmission. Reduction in CD47 expression improved social novelty preference deficits in 16p11.2 mice. These findings demonstrate that CD47 is associated with the ASD phenotypes in the 16p11.2 deletion mice and could be a promising target for the development of treatment for ASD.

Keywords:  16p11.2 deletion syndrome; CD47; autism; microglia; phagocytosis

DOI:  https://doi.org/10.1073/pnas.2411080122
Theranostics. 2025 ;15(10): 4763-4784

Microglial Lcn2 knockout enhances chronic intracerebral hemorrhage recovery by restoring myelin and reducing inflammation.

Li Wang, Lei Zhang, Kai Wang, Jun He, Liang Yuan, Yangang Wang, Weihao Lv, Zehan Zhang, Yuan Feng, Hongchen Zhang, Min Zhang, Rui Lv, Ya-Nan Dou, Xiaowei Fei, Jialiang Wei.

  Rationale: Damage to white matter and myelin poses a significant challenge to neurological recovery in the chronic phase of intracerebral hemorrhage (ICH). The repair of myelin damage post-ICH largely depends on the activation and differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes, a process that is significantly influenced by the inflammatory microenvironment. Lipocalin-2 (Lcn2) regulate phenotypic transformation of microglia and thus modulates inflammation. However, the exact role of Lcn2 in facilitating myelin recovery during the chronic phase of ICH remains to be fully understood. Methods: To create the ICH model, autologous blood from male C57BL/6 and Lcn2fl/flCx3cr1Cre mice was utilized. Behavioral tests were conducted to evaluate neurological recovery. The differentiation of OPCs and extent of myelin recovery were assessed using OPC and myelin markers. A multi-factor inflammatory chip was employed to investigate potential molecular regulatory mechanisms. Additionally, the Lcn2 inhibitor ZINC-94/89 was administered to explore its potential in targeting Lcn2 for enhancing myelin recovery during the chronic phase of ICH. Results: Knocking out Lcn2 in microglia significantly improved behavioral performance in chronic ICH mice, reduced inflammatory response, and enhanced myelin recovery. Both in vivo and in vitro experiments confirmed that Lcn2 knockout promoted microglia transformation to the M2 phenotype and enhanced OPCs differentiation. Mechanistically, Lcn2 knockout might affect Gdf-1 secretion in BV2 cells by modulating the JAK/STAT signaling pathway. Treatment with JAK inhibitors decreased Gdf-1 expression in BV2 cells, inhibiting OPCs migration and differentiation. Additionally, phosphorylation of Stat3 at Thr705 plays a critical role in enhancing Gdf-1 transcription and translation. Administration of the Lcn2 inhibitor ZINC-94/89 significantly improved behavioral performance, reduced inflammatory response, and promoted myelin recovery in chronic ICH mice. Conclusions: Lcn2 is crucial for myelin recovery in the chronic phase of ICH by modulating microglial phenotypes, thereby enhancing the migration and differentiation of OPCs. Administering an Lcn2 inhibitor early on could serve as a novel and effective strategy to boost recovery during this phase.

Keywords:  ICH; Lcn2; OPCs; microglia; myelin

DOI:  https://doi.org/10.7150/thno.109440
Cell Rep. 2025 Apr 11. pii: S2211-1247(25)00330-4. [Epub ahead of print]44(4): 115559

Cannabinoid CB2 receptor controls chronic itch by regulating spinal microglial activation and synaptic transmission.

Kangtai Xu, Xuefei Liu, Qian Zeng, Yaqi Liu, Leyan Shan, Luyao Ji, Yifei Wu, Jiawei Wu, Yiming Chen, Yitong Li, Songqiang Huang, Changyu Jiang, Xin Hong, Chaoran Wu, Zilong Wang.

  Chronic itch is a devastating clinical condition, and its central mechanisms remain poorly understood. We reported that spinal cannabinoid receptor type 2 (CB2R) activation exerts antipruritic effects and that itch escalates in mice lacking Cnr2 in mouse models of dermatitis and psoriasis. In the spinal cord, CB2R is mainly expressed in microglia, and microglial ablation or inhibition attenuated chronic itch, suggesting that microglial activation contributes to chronic itch. Particularly, conditional Cnr2 deletion in microglia also exacerbated chronic itch in mice. Single-cell RNA sequencing and molecular mechanistic studies suggest that CB2R activation reprogrammed microglia by inducing anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) and reducing itch-related p38 and signal transducer and activator of transcription 1 (STAT1) phosphorylation. Finally, CB2R activation suppressed neuronal excitability and synaptic transmission in gastrin-releasing peptide (GRP)/GRP receptor (GRPR) interneurons and ascending projection neurons by inhibiting microglia-derived cytokines. These findings demonstrate that microglial activation contributes to chronic itch, while CB2R activation in microglia alleviates chronic itch via neuro-immune interactions.

Keywords:  CP: Neuroscience; GRPR; SOCS3; STAT1/p38 pathway; cannabinoid receptor type 2; central sensitization; dermatitis; itch; microglia; neuro-immune interactions; spinal cord; synaptic transmission

DOI:  https://doi.org/10.1016/j.celrep.2025.115559
Sci Rep. 2025 Apr 14. 15(1): 12818

Divergent neurodegeneration associations with choroid plexus volume and degree of calcification in cognitively normal APOE ε4 carriers and non-carriers.

Ilker Ozsahin, Xiuyuan Wang, Liangdong Zhou, Ke Xi, Seyed Hani Hojjati, Emily Tanzi, Thomas Maloney, Edward K Fung, Jonathan P Dyke, Kewei Chen, Silky Pahlajani, Laura Beth McIntire, Ana Paula Costa, William Jones Dartora, Qolamreza R Razlighi, Lidia Glodzik, Yi Li, Gloria C Chiang, Henry Rusinek, Mony J de Leon, Tracy A Butler.

  Choroid plexus (CP), best known for producing CSF, also regulate inflammation and clear metabolic waste to maintain brain homeostasis. CP dysfunction is implicated in Alzheimer's Disease (AD), with MRI studies showing CP enlargement in AD. The basis for CP enlargement is unknown. We hypothesized that calcium deposition within CP, which increases with aging and in certain neurodegenerative conditions, might underlie pathologic CP enlargement and be linked to neurodegeneration. In 166 cognitively normal participants, we used multimodal imaging to examine CP structure (MRI-measured overall volume, CT-measured calcium volume), PET-measured Aβ, age, and APOE genotype as predictors of neurodegeneration, indexed as hippocampal volume. CP enlargement was associated with reduced hippocampal volume, particularly in APOE4 carriers. CP calcium was not independently associated with hippocampal volume. However, a significant interaction revealed APOE4 genotype-specific associations between CP calcium and neurodegeneration, with APOE4 carriers showing greater hippocampal volumes in association with greater CP calcium-opposite to our hypothesis. Results suggest that a factor other than calcium drives pathologic CP enlargement associated with neurodegeneration, with this factor especially important in APOE4 carriers. Candidate factors include lipids and inflammatory cells, which are known to accumulate in CP and be regulated by APOE. Our findings highlight CP as a critical locus for studying AD pathogenesis and the mechanisms by which APOE4 promotes AD.

Keywords:  APOE; Calcification; Choroid plexus; Neurodegeneration; PiB PET

DOI:  https://doi.org/10.1038/s41598-025-97409-1
Alzheimers Dement. 2025 Apr;21(4): e70120

Synergistic reduction in interfacial flexibility of TREM2R47H and ApoE4 may underlie AD pathology.

Emma E Lietzke, David Saeb, Emma C Aldrich, Kimberley D Bruce, Kayla G Sprenger.

   BACKGROUND: The strongest genetic drivers of late-onset Alzheimer's disease (AD) are apolipoprotein E4 (ApoE4) and TREM2R47H. Despite their critical roles, the mechanisms underlying their interactions remain poorly understood.
METHODS: We conducted microsecond-long molecular dynamics simulations of TREM2-ApoE complexes, including TREM2R47H, validating our findings through comparison with published experimental data on TREM2-ApoE binding interactions.
RESULTS: Our simulations reveal TREM2WT can sample an "open" CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2WT exhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2R47H's CDR2 may explain its reduced ligand-binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2-ApoE2 complexes, which is absent with ApoE4. TREM2R47H and ApoE4 mutually rigidify each other, suppressing interfacial flexibility.
DISCUSSION: Our findings suggest mechanisms underlying ApoE2's neuroprotective functions, ApoE4's pathogenicity, and the synergistic effects of ApoE4 and TREM2R47H in AD. TREM2WT's flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2R47H-ApoE4 interactions may drive pathogenic signaling.
HIGHLIGHTS: TREM2WT samples diverse CDR2 conformations, challenging prior assumptions that an "open" CDR2 state is solely pathogenic. ApoE2 promotes dynamic reconfiguration of TREM2-ApoE2 complexes, preserving TREM2WT's flexibility. ApoE4's hinge forms a unique binding pocket that enhances TREM2 binding. The TREM2R47H-ApoE4 complex exhibits mutual rigidity, suppressing CDR2 and hinge flexibility.

Keywords:  Alzheimer's disease; ApoE; TREM2; interfacial flexibility; molecular dynamics

DOI:  https://doi.org/10.1002/alz.70120
Neurobiol Stress. 2025 May;36 100721

Sex-specific regulation of microglial MyD88 in HMGB1-Induced anxiety phenotype in mice.

Ashleigh Rawls, Julia Dziabis, Dang Nguyen, Dilara Anbarci, Madeline Clark, Grace Zhang, Kafui Dzirasa, Staci D Bilbo.

Stress is a significant risk factor for the development and recurrence of anxiety disorders. Stress can profoundly impact the immune system, and lead to microglial functional alterations in the medial prefrontal cortex (mPFC), a brain region involved in the pathogenesis of anxiety. High mobility group box 1 protein (HMGB1) is a potent pro-inflammatory stimulus and danger-associated molecular pattern (DAMP) released from neuronal and non-neuronal cells following stress. HMGB1 provokes pro-inflammatory responses in the brain and, when administered locally, alters behavior in the absence of other stressors. In this study, we administered dsHMGB1 into the mPFC of male and female mice for 5 days to investigate the cellular and molecular mechanisms underlying HMGB1-induced behavioral dysfunction, with a focus on cell-type specificity and potential sex differences. Here, we demonstrate that dsHMGB1 infusion into the mPFC elicited behavior changes in both sexes but only altered microglial morphology robustly in female mice. Moreover, preventing microglial changes with cell-specific ablation of the MyD88 pathway prevented anxiety-like behaviors only in females. These results support the hypothesis that microglial MyD88 signaling is a critical mediator of HMGB1-induced stress responses, particularly in adult female mice.

DOI: https://doi.org/10.1016/j.ynstr.2025.100721
PLoS Biol. 2025 Apr 15. 23(4): e3003073

Monocyte-secreted Wnt reduces the efficiency of central nervous system remyelination.

Bianca M Hill, Rebecca K Holloway, Lindsey H Forbes, Claire L Davies, Jonathan K Monteiro, Christina M Brown, Jamie Rose, Neva Fudge, Pamela J Plant, Ayisha Mahmood, Koroboshka Brand-Arzamendi, Sarah A Kent, Irene Molina-Gonzalez, Stefka Gyoneva, Richard M Ransohoff, Brian Wipke, Josef Priller, Raphael Schneider, Craig S Moore, Veronique E Miron.

The regeneration of myelin in the central nervous system (CNS) reinstates nerve health and function, yet its decreased efficiency with aging and progression of neurodegenerative disease contributes to axonal loss and/or degeneration. Although CNS myeloid cells have been implicated in regulating the efficiency of remyelination, the distinct contribution of blood monocytes versus that of resident microglia is unclear. Here, we reveal that monocytes have non-redundant functions compared to microglia in regulating remyelination. Using a transgenic mouse in which classical monocytes have reduced egress from bone marrow (Ccr2-/-), we demonstrate that monocytes drive the timely onset of oligodendrocyte differentiation and myelin protein expression, yet impede myelin production. Ribonucleic acid sequencing revealed a Wnt signature in wild-type mouse lesion monocytes, which was confirmed in monocytes from multiple sclerosis white matter lesions and blood. Genetic or pharmacological inhibition of Wnt release by monocytes increased remyelination. Our findings reveal monocytes to be critical regulators of remyelination and identify monocytic Wnt signaling as a promising therapeutic target to inhibit for increased efficiency of CNS regeneration.

DOI: https://doi.org/10.1371/journal.pbio.3003073
J Lipid Res. 2025 Apr 16. pii: S0022-2275(25)00069-0. [Epub ahead of print] 100809

Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis.

Jue Zhang, Jackie Chang, Vaya Chen, Mirza Ahmar Beg, Wenxin Huang, Lance Vick, Yaxin Wang, Heng Zhang, Erin Yttre, Ankan Gupta, Mark Castleberry, Ziyu Zhang, Wen Dai, Jieqing Zhu, Shan Song, Moua Yang, Ashley Kaye Brown, Zhen Xu, Yan-Qing Ma, Brian C Smith, Jacek Zielonka, James G Traylor, Cyrine Ben Dhaou, A Wayne Orr, Weiguo Cui, Yiliang Chen.

  Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic phenotypes in macrophages, accelerating the progression of atherosclerosis. Our previous studies demonstrated that oxLDL binds to its receptor CD36, stimulating mitochondrial reactive oxygen species (mtROS), which are critical in atherosclerosis development. However, the mechanisms underlying mtROS induction and their effects on macrophage cellular functions remain poorly understood. Macrophages rely on phagocytosis to clear pathogens, apoptotic cells, or other particles, a process critical for tissue homeostasis. Dysregulated or excessive particle ingestion, a key step in phagocytosis, can lead to lipid overloading and foam cell formation, a hallmark of atherosclerosis. In this study, we showed that macrophages pre-treated with oxLDL exhibit increased particle ingestion, a phagocytic response significantly attenuated in Cd36-null macrophages. Further investigations revealed that oxLDL-induced phagocytosis depends on mtROS, as their suppression inhibited the process. In vivo, atherosclerosis-prone Apoe-null mice on a high-fat diet exhibited increased mtROS levels and enhanced phagocytic activity in aortic foamy macrophages compared to those from chow diet-fed mice, supporting a role of mtROS in promoting lesional macrophage phagocytosis. Mechanistically, we identified a novel signaling pathway whereby oxLDL/CD36 interaction induces the translocation of the cytosolic enzyme pyruvate kinase muscle 2 (PKM2) to mitochondria. Disruption of PKM2 mitochondrial translocation using siRNA knockdown or a specific chemical inhibitor reduced mtROS production and attenuated oxLDL-induced phagocytosis. In conclusion, our findings reveal a novel oxLDL-CD36-PKM2 signaling axis that drives mtROS production and phagocytosis in atherogenic macrophages.

Keywords:  CD36; PKM2; atherosclerosis; glycolysis; macrophages; mitochondria; phagocytosis; reactive oxygen species

DOI:  https://doi.org/10.1016/j.jlr.2025.100809
J Neurosci Methods. 2025 Apr 10. pii: S0165-0270(25)00087-1. [Epub ahead of print]419 110446

μGlia-Flow, an automatic workﬂow for microglia segmentation and classification.

Huangrui Xiong, Siling Zheng, Xiuhong Qi, Ji Liu.

   BACKGROUND: Microglia are important immune cells in the central nervous system, playing a key role in various pathological processes. The morphological diversity of microglia is closely linked to the development of brain diseases, yet accurate segmentation and automatic classification of microglia remain challenging.
NEW METHOD: We proposed a workflow, μGlia-Flow, which integrates both segmentation and classification for microglia analysis. The Frangi filtering algorithm was employed for branch segmentation, and an edge-guided attention TransUNet (EGA-Net) was used for soma segmentation. A Vision Transformer (ViT) network was applied to classify different morphologies.
RESULTS: The Frangi filtering algorithm produces more complete branches with smoother edges and clearer structures. The EGA-Net improves Dice and IoU scores by 4.02 % and 6.75 %, respectively. ViT achieves over 99 % precision in classification. Post-processing reveals decreasing complexity during activation, validating the accuracy of μGlia-Flow.
COMPARISON WITH EXISTING METHODS: μGlia-Flow introduces deep learning, significantly improving segmentation accuracy and addressing the parameter dependency of existing classification methods.
CONCLUSION: we present an automatic workflow for segmenting and classifying microglia, providing a powerful tool for different morphology analysis.

Keywords:  Cell segmentation; Edge-guided attention; Frangi filter; Image classification; Microglia

DOI:  https://doi.org/10.1016/j.jneumeth.2025.110446
Theranostics. 2025 ;15(10): 4673-4692

A new nano-encapsulated TSPO ligand reduces neuroinflammation and improves cognitive functions in Alzheimer's disease model.

Antonella Casamassa, Paola Brancaccio, Virginia Campani, Angela Corvino, Serenella Anzilotti, Giovanni Pecoraro, Giorgia Andreozzi, Raffaella Daniele, Ilaria Piccialli, Anna Pannaccione, Pierluigi Reveglia, Lucia Lecce, Carmela Paolillo, Ferdinando Fiorino, Giuseppe De Rosa, Giuseppe Caliendo, Lucio Annunziato, Giuseppe Pignataro.

  Rationale: The translocator protein 18 kDa (TSPO) is mainly expressed on the outer mitochondrial membrane and is implicated in inflammation, cell survival, and proliferation. TSPO expression in activated microglia is upregulated in Alzheimer's disease (AD), representing both a biomarker and therapeutic target for neuroinflammation. Methods: We synthesized a new TSPO ligand, TEMNAP, a hybrid of temazepam, a compound well known for its ability to bind TSPO, and naproxen, a drug with anti-inflammatory properties that is potentially useful to mitigate neuroinflammation. TEMNAP was encapsulated in a self-assembling nanoparticle transferrin-targeted (SANP-TF-TEMNAP) for brain delivery. The effectiveness of TEMNAP in mitigating inflammatory processes and cognitive behavior was investigated in genetically modified Tg2576 mice, a model of Alzheimer's disease. Its effect on neuroinflammation has also been explored in lipopolysaccharide-activated BV2 microglial cells. Results: SANP-TEMNAP significantly reduced the expression of proinflammatory markers in activated microglia, and this effect was abrogated by TSPO silencing. More importantly, TEMNAP was mass-spectrometrically detected in the hippocampus and cortex of Tg2576 mice after SANP-TF-TEMNAP intraperitoneal administration, preventing hippocampal neuroinflammation and improving cognitive function. Conclusions: These results emphasize the following: (i) the role of transferrin-conjugated self-assembling nanoparticles (SANP-TF) as CNS nanovectors, and (ii) the potential therapeutic effectiveness of peripherally administered SANP-TF-TEMNAP in preventing neuroinflammation associated with cognitive decline.

Keywords:  Alzheimer's disease; TSPO; nanovectors; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.7150/thno.106083
Sci Prog. 2025 Apr-Jun;108(2):108(2): 368504251336080

Sex differences in brain iron deposition and microglial ferritin in Alzheimer's disease.

Syed Mushfiqur Rahman, Chunfeng Tan, Akiyoshi Kakita, Jose Felix Moruno-Manchon.

  ObjectiveIron is the most abundant metal in the human brain, and plays a crucial role in many biological processes. However, disruptions in brain iron metabolism can lead to iron buildup, which occurs with aging and is linked to several brain disorders, including Alzheimer's disease. Microglia, the brain's resident immune cells, have the highest capacity to store iron, which is stored intracellularly within ferritin complexes. Importantly, women are at a higher risk of developing Alzheimer's disease and experience faster disease progression compared to men.MethodsWe used postmortem brain samples from patients with Alzheimer's disease and small vessel disease patients of both sexes for immunohistochemical studies. Samples were stained with the Prussian blue method to visualize iron deposits and with antibodies against the microglia marker Iba1 and ferritin light chain.ResultsOur study reveals that the number of iron deposits and the levels of ferritin light chain in microglia are positively correlated in men with Alzheimer's disease, but negatively correlated in women. There is no correlation between brain iron deposition and ferritin in samples from patients with small vessel disease of both sexes.ConclusionsThese results could inform more tailored approaches to the treatment and management of Alzheimer's disease based on sex-specific differences in brain iron metabolism and microglial iron storage capacity.

Keywords:  Brain iron accumulation; ferritin; microglia; sex differences

DOI:  https://doi.org/10.1177/00368504251336080
J Neuroimmune Pharmacol. 2025 Apr 16. 20(1): 40

Evaluation of the Anti-Inflammatory Effects of Novel Fatty Acid-Binding Protein 4 Inhibitors in Microglia.

Yi Ling Low, Ethan Kreutzer, Indu R Chandrashekaran, Luke A Adams, Jason Pun, Bradley C Doak, Yijun Pan, Jennifer L Short, Martin J Scanlon, Joseph A Nicolazzo.

  Fatty acid-binding protein 4 (FABP4) is a key lipid binding protein expressed in microglia, which has been demonstrated to play a critical role in microglial-mediated neuroinflammation, a component of many neurodegenerative diseases. Compounds able to inhibit the function of FABP4 have shown promise in reducing microglial-mediated neuroinflammation, however, their physicochemical properties would prevent their ability to be easily formulated and traverse the blood-brain barrier (BBB) in order to access microglial FABP4. To this end, this study assessed the ability of a series of FABP4 inhibitors, with more desirable physicochemical properties, to attenuate microglial inflammation in an in vitro setting. Four inhibitors with varying affinity to FABP4, as measured by isothermal titration calorimetry (MFP-0011462, MFP-0012314, MFP-0012318, and MFP-0012328), were assessed for their ability to induce toxicity and attenuate reactive oxygen species (ROS) generation and tumour necrosis factor-α (TNF-α) release from lipopolysaccharide (LPS)-activated BV-2 microglia. All FABP4 inhibitors were determined to be soluble in the aqueous buffers at the highest concentration used in the assays (100 µM). Isothermal titration calorimetry demonstrated that the compounds had varying affinities for FABP4 (KD values of 316 nM to > 100 µM). The ability of FABP4 inhibitors to reduce LPS-mediated ROS production aligned with their KD for FABP4, with the most effective inhibitor (MFP-0012328) also able to reduce TNF-α production (by RT-qPCR) and TNF-α release from LPS-activated BV-2 cells by 17% and 25%, respectively. These studies have demonstrated that a series of FABP4 inhibitors with more appropriate physicochemical properties for BBB penetration are able to reduce microglial-mediated inflammation, which may be of benefit in diseases where overactivation of microglia leads to neurodegeneration.

Keywords:  Fatty acid-binding protein 4; Microglia; Neuroinflammation; Reactive oxygen species; Tumour necrosis factor alpha

DOI:  https://doi.org/10.1007/s11481-025-10191-9
Brain Res. 2025 Apr 16. pii: S0006-8993(25)00208-2. [Epub ahead of print] 149649

Menopause triggers microglia-associated neuroinflammation in Parkinson's disease.

Sehar Usman, Amal Chandra Mondal.

  Microglia, immune cells of the brain, can drive neurodegenerative diseases like Parkinson's disease (PD). The resting microglia can polarize into two extremes, either proinflammatory M1 or anti-inflammatory M2 phenotype under a specific microenvironment. Different transcriptional factors and the release of various cytokines characterize these states. The released proinflammatory markers from M1 microglia lead to neuroinflammation that ultimately causes irreversible loss of dopaminergic neurons in PD patients, on the contrary, the M2 microglia possess neuroprotective activity. PD is caused by aggregation and misfolding of α-synuclein in the affected dopaminergic neurons. The misfolded α-synuclein is cytotoxic and can propagate like a prion from one cell to the other, acting like a template that can initiate the conversion of normal proteins into abnormal conformation. The extracellular α-synuclein can interact and polarize the microglia into the M1 phenotype resulting in inflammation, thereby driving the progression of PD. The progression of neuroinflammation-mediated neurodegeneration in PD is seen higher in menopausal women; likely due to the low circulating estrogen levels. Estrogen hormones possess neuroprotective activity, and one of the ways is that they can polarize the microglia into M2 phenotypes and reduce α-synuclein-mediated microglial activation. A detailed understanding of the signaling mechanisms underlying microglial polarization between M1 and M2 phenotypes is crucial for identifying druggable targets to reduce PD symptoms, including in menopausal women.

Keywords:  Estrogen; Menopause; Microglia; Neuroinflammation; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.brainres.2025.149649
Brain Behav Immun. 2025 Apr 15. pii: S0889-1591(25)00156-4. [Epub ahead of print]128 307-322

Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors.

L H D Le, A M Feidler, L Calcines Rodriguez, M Cealie, E Plunk, H Li, K Kara-Pabani, C Lamantia, M K O'Banion, A K Majewska.

  Norepinephrine (NE) is a potent anti-inflammatory agent in the brain. In Alzheimer's disease (AD), the loss of NE signaling heightens neuroinflammation and exacerbates amyloid pathology. NE inhibits surveillance activity of microglia, the brain's resident immune cells, via their β2 adrenergic receptors (β2ARs). Here, we investigate the role of microglial β2AR signaling in AD pathology in the 5xFAD mouse model of AD. We found that loss of cortical NE projections preceded the degeneration of NE-producing neurons and that microglia in 5xFAD mice, especially those microglia that were associated with plaques, significantly downregulated β2AR expression early in amyloid pathology. Importantly, dampening microglial β2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial β2AR signaling attenuated amyloid pathology. Our results suggest that microglial β2AR could be explored as a potential therapeutic target to modify AD pathology.

Keywords:  Amyloid pathology; Aβ plaques; Locus coeruleus; Microglia; Neurodegeneration; Neuroinflammation; Noradrenergic signaling; Norepinephrine; Plaque-associated microglia; Two-photon microscopy

DOI:  https://doi.org/10.1016/j.bbi.2025.04.022
CNS Neurosci Ther. 2025 Apr;31(4): e70394

Depletion of HSP60 in Microglia Leads to Synaptic Dysfunction and Depression-Like Behaviors Through Enhanced Synaptic Pruning in Male Mice.

Wenhui Zhu, Jinlong Chang, Liusuyan Tian, Xiuyan Yang, Weifen Li.

   AIMS: Microglia, as resident macrophages in the brain, play an important role in depression. Heat shock protein 60 (HSP60), as a chaperone protein, plays a role in cell stress. However, the role of microglial HSP60 in depression remains unclear.
METHODS: CX3CR1-CreER was used to generate microglial-specific HSP60 knockout (HSP60 cKO) mice. Behavioral tests, western blotting, Golgi staining, biochemical assays, and proteomics were employed to assess depression-like symptoms, microglial activation, and synaptic changes.
RESULTS: HSP60 cKO male mice exhibited depressive-like behaviors, without anxiety-like behavior, including increased immobility in the forced swimming and tail suspension tests, reduced sucrose preference, and elevated corticosterone (CORT) levels, indicating HPA axis activation. Microglial activation was confirmed by the increased expression levels of CD68 and CD86, the elevated transcription of the cybb gene, and reduced branch complexity. Enhanced phagocytosis of excitatory synapses, reduced dendritic spine density, and decreased glutamate levels were observed, with downregulation of synaptic proteins (AMPAR2, Synapsin-1, PSD95), indicating dysregulated synaptic pruning. Moreover, GO analysis showed 20 significant differentially expressed proteins (DEPs) from proteomics are associated with the presynaptic endosome, which plays a crucial role in maintaining synaptic function. Treatment with PLX3397, a CSF1R inhibitor, alleviated depressive-like behaviors and restored synaptic density in HSP60 cKO male mice.
CONCLUSIONS: HSP60 deletion in microglia leads to overactivation of microglia, impaired synaptic function, and depression-like behaviors, highlighting the importance of microglial homeostasis in mood regulation and the potential therapeutic role of microglial modulation.

Keywords:  HSP60; depression; microglia; phagocytosis; synapse

DOI:  https://doi.org/10.1111/cns.70394