bims-microg 2025-12-28 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–12–28
eleven papers selected by
Marcus Karlstetter, Universität zu Köln

Smoothened-mediated signaling contributes to immune and non-immune functions of microglia.
Microglial TIA1-mediated stress granules promote neuroinflammation and aggravate neuron loss in mice after ischemic stroke by inhibiting IGF2 signaling.
Microglial mechanisms of viable retinal ganglion cell elimination.
The Alzheimer's disease risk genes MS4A4A and MS4A6A cooperate to negatively regulate TREM2 and microglia states.
FoxO1, together with Notch1, promotes microglial activation to induce pathological changes in the retinal vasculature under hypoxia.
Brain-infiltrated monocyte macrophages in a rat model of temporal lobe epilepsy: revisiting the pro-inflammatory paradigm.
ANXA1 regulates microglia polarization and autophagy via PI3K/Akt/mTOR pathway to reduce inflammatory injury after cerebral ischemia-reperfusion.
Chlorogenic acid exerts anti-inflammation and neuroprotective effect in pentylenetetrazole-induced epilepsy mouse model by regulating microglia polarization via Nrf2/HO-1 pathway.
Sex-dependent immune activation shapes disease progression in a model of Parkinson's disease.
Flipping the Switch: MeCP2-Mediated Lactylation Rewires Microglial Metabolism and Inflammation via the HK2/mTOR Axis in Poststroke Neuroinflammation.
Mapping microglial mechanisms in Alzheimer's disease: a comprehensive analysis.

Brain Behav Immun. 2025 Dec 18. pii: S0889-1591(25)00468-4. [Epub ahead of print]132 106226

Smoothened-mediated signaling contributes to immune and non-immune functions of microglia.

Adil El Mesaoudi, Abdelmoumen Kassoussi, Amina Zahaf, Maysoun Ayadi, Sara Naglieri, Corentine Marie, Ferechte Razavi, Pierre Bobé, Jelena Martinovic, Carlos Parras, Elisabeth Traiffort.

  The brain resident macrophages, or microglia, display essential functions ranging from contributing to brain development to triggering innate immune responses. The different ways microglia operate reflect their varying context-dependent states. However, the mechanisms that control these states remain largely unknown. Here, we identified a small population of microglia that express Smoothened (Smo), the well-known key component of the Hedgehog signaling pathway. Our experiments involving both loss and gain of function, demonstrate that the intrinsic activity of microglial Smo is mostly associated with the effective initiation of appropriate innate immune responses to pathogens and the control of microglia phagocytic activities. Microglial Smo activity is also involved in the appearance of amoeboid microglia that transiently arise in the developing white matter during the perinatal period. Moreover, the exogenous and Hedgehog signaling-independent activation of microglial Smo counteracts the molecular cascades occurring in microglia under inflammatory conditions. All these data indicate previously unrecognized roles for the Smo receptor and could lead to further research to discover a new category of non-canonical Smo agonists that might specifically regulate microglial states.

Keywords:  Congenital CMV infection; Developmental myelination; Innate immune response; Microglia; Pathogen phagocytosis; Smoothened; Transient amoeboid microglia

DOI:  https://doi.org/10.1016/j.bbi.2025.106226
Theranostics. 2026 ;16(5): 2627-2648

Microglial TIA1-mediated stress granules promote neuroinflammation and aggravate neuron loss in mice after ischemic stroke by inhibiting IGF2 signaling.

Yiming Qian, Hong Yu, Jianhong Dong, Jinyuan Liu, Jiaqi Han, Tianwen Zheng, Wei Zhang, Lipei Wang, Zhihui Huang, Ying Wang.

  Rationale: Microglia cells as niche homeostasis monitor with rapid responses to acute ischemic stroke (IS). T-cell intracellular antigen 1 (TIA1), a core component of stress granules (SGs), is involved in cellular stress responses such as hypoxia, but its roles and mechanisms in regulating microglial responses during IS remain unclear. Methods: To evaluate the function of microglial TIA1 in IS, we established a mouse model of IS by using photothrombotic method. Furthermore, conditional knockout (CKO) of Tia1 in microglia mice (Tia1 Cx3cr1-CKO mice) was generated and then Tia1 Cx3cr1-CKO IS mice and their littermate controls (Tia1 f/f IS mice) were used as experimental subjects. The behavioral tests, immunostaining, Laser speckle contrast imaging (LSCI), TTC staining, Nissl staining, quantitative real-time PCR (qPCR) and Western blotting were used to assess the effects of microglial Tia1 deletion in IS progression. In vitro, we utilized the microglia cell line (HMC3 cells) and primary cultured microglia to establish an OGD model, and generated stable TIA1-knockdown or TIA1-overexpressing HMC3 cell lines, and employed a co-culture system of HMC3 and N2a cells to further explore the roles of microglial Tia1 signaling in IS. Through RNA sequencing (RNA-seq) of control HMC3 cells and Tia1-knockdown HMC3 cells, we investigated in depth the role and molecular mechanism of TIA1-mediated insulin-like growth factor 2 (IGF2) signaling pathway in microglia during IS progression. Results: Microglial TIA1 was significantly upregulated in mice during the acute phase of IS. Microglial Tia1 knockout suppressed microglial pro-inflammatory responses, enhanced anti-inflammatory responses, promoted phagocytic clearance of infarct debris, alleviated neuronal death, and improved motor deficits in post-IS mice. In vitro, TIA1 promoted pro-inflammatory responses to exacerbate neuronal cell death and inhibited phagocytic ability of microglia cells after OGD. Mechanistically, Tia1 deletion in microglia impaired SG formation, reduced sequestration of Igf2 mRNA into SGs, upregulated IGF2 expression, and IGF2 signaling enhanced anti-inflammatory responses and phagocytic capacity while suppressing pro-inflammatory activation in microglia. Conclusions: These findings identify a previously unrecognized function of microglial TIA1 in modulating microglia homeostasis and sustaining pro-inflammatory responses via SGs-mediated Igf2 mRNA sequestration after IS, providing a novel therapeutic target for IS treatment.

Keywords:  IGF2; TIA1; ischemic stroke; neuroinflammation; stress granules

DOI:  https://doi.org/10.7150/thno.122008
Front Cell Neurosci. 2025 ;19 1719791

Microglial mechanisms of viable retinal ganglion cell elimination.

Navita N López, Yésica Landaverde Rodríguez, Monica L Vetter.

  Microglia can selectively phagocytose live neurons during normal development and also in response to stress, injury or disease by recognizing phagocytic cues to target cells for elimination. In the developing retina at embryonic stages we previously found that microglia refine retinal ganglion cell (RGC) numbers by targeting non-apoptotic newborn RGCs for phagocytosis, utilizing complement receptor 3 (CR3) to recognize and eliminate RGCs. Here, we investigate additional phagocytic mechanisms and cues that microglia utilize to clear a subset of viable RGCs. Our findings indicate that both Mer tyrosine kinase (Mertk) and CR3 are required for clearance of a subpopulation of embryonic RGCs. In Mertk/CR3 double knockouts, we show that C1q-tagged RGCs accumulate and excess RGCs persist indicating failure of normal clearance by microglia. We also show that microglia target RGCs that have phosphorylated c-JUN (p-cJUN) expression, suggesting stress pathway activation. RGCs with p-cJUN expression also accumulate in Mertk/CR3 double knockout retinas, but this appears to resolve by P0, suggesting this is a transient stress state exhibited by a subset of RGCs that remain viable. By depleting microglia we establish that microglia are not required for p-cJUN induction in RGCs but show that they are the sole source of complement protein C1q, which marks these cells for elimination. Altogether the data suggests that a subset of stressed RGCs are recognized by local microglia that tag them with opsonins for removal using specific recognition receptors.

Keywords:  CR3; MERTK; complement receptor 3; microglia; phagocytosis; retina

DOI:  https://doi.org/10.3389/fncel.2025.1719791
Neuron. 2025 Dec 22. pii: S0896-6273(25)00895-5. [Epub ahead of print]

The Alzheimer's disease risk genes MS4A4A and MS4A6A cooperate to negatively regulate TREM2 and microglia states.

Dalya Rosner, Jiahong Sun, Rita Cacace, Angie Yee, Chaitanya Wagh, Anna Rychkova, Mariah Dunlap, Daniel Gulbranson, Adiljan Ibrahim, Xiaoting Wang, Rebecca Wang, Alice Buonfiglioli, Muhammad Alhawagri, Phil Kong, Marina Roell, Wei-Hsien Ho, Belvin Gong, Heidi Denton, Giacomo Muscarnera, Tim Meese, Malak El-Khatib, Daniel Bermingham, Elias Kahn, Francesca Cignarella, Herve Rhinn, Zia Khan, Tina Schwabe, Karpagam Srinivisan, Ananya Mitra, Lotje de Witte, Peter Heutink, Renzo Mancuso, Ilaria Tassi, Julia Kuhn, Hua Long, Sara Kenkare-Mitra, Arnon Rosenthal.

  Genetic variations in MS4A4A and MS4A6ATriggering receptor expressed on myeloid cells 2 (TREM2) are linked to the regulation of cerebrospinal-fluid-soluble TREM2 levels and are associated with Alzheimer's disease (AD) risk and progression. By modulating MS4A4A using knockout, overexpression, and degrading antibodies in macrophages, microglia, non-human primates (NHPs), and a mouse model of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the transmembrane and soluble TREM2 proteins. Additionally, MS4A4A limits microglia viability, phagocytosis, and lysosomal function, processes that contribute to disease pathology. Mechanistically, we find that MS4A4A restrains TREM2 by an indirect mechanism: MS4A4A interacts with MS4A6A and protects it from degradation. MS4A6A, in turn, forms a complex with and blocks the co-receptor DNAX-activating protein of 12 kDa (DAP12), which modulates the levels of TREM2 and other receptors. Taken together, the data indicate that MS4A4A and MS4A6A are cooperative post-transcriptional negative regulators of TREM2 and microglial function as well as potential drug targets for AD.

Keywords:  Alzheimer’s disease; DAP12; MS4A; MS4A4A; MS4A6A; TREM2; TYROBP; macrophage; microglia; neurodegeneration

DOI:  https://doi.org/10.1016/j.neuron.2025.11.022
Cell Mol Life Sci. 2025 Dec 21.

FoxO1, together with Notch1, promotes microglial activation to induce pathological changes in the retinal vasculature under hypoxia.

Xiyu Wu, Junbin Liu, Haoxian Zhu, Guanrong Wu, Xinyu Chen, Tai Guo, Xiang Fang, Qianli Meng.

  Microglia, the resident immune cells in the retina, play important roles in the retinopathies. Although the role of the Notch signaling pathway in microglial activation and inflammation in neuroinflammatory diseases has been extensively studied, less is known about the effects of Notch signaling on retinal microglia in ischemic retinopathies. Here, we demonstrated that hypoxia triggers Notch1-FoxO1 nuclear translocation in retinal microglia, driving proinflammatory and proangiogenic phenotypes that disrupt vascular homeostasis. We first showed that hypoxia induced microglial activation and upregulated the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α and proangiogenic factors FGF2, VEGF, and PDGF-β, which promoted retinal vascular endothelial cell dysfunction, marked by increased cellular permeability, migration, and tube formation. We then identified the Jagged1-Notch1 pathway and FoxO1 nuclear translocation as a pivotal signaling axis driving this proinflammatory microglial response under hypoxia. Finally, we demonstrated the therapeutic potential of this axis by showing that inhibition of Notch1 or FoxO1 in hypoxia-activated microglia and in the eyes of oxygen-induced retinopathy mice ameliorated both inflammation and pathological neovascularization in the retina. These findings suggest that FoxO1, together with Notch1, promotes microglial activation to induce retinal vasculopathy under hypoxia, indicating that targeting the Notch1-FoxO1 axis may be a therapeutic strategy for ischemic retinopathies.

Keywords:  FoxO1; Hypoxia; Ischemic retinopathy; Microglia; Notch1 pathway; Retinal vascular endothelial cells

DOI:  https://doi.org/10.1007/s00018-025-06024-w
Front Immunol. 2025 ;16 1695856

Brain-infiltrated monocyte macrophages in a rat model of temporal lobe epilepsy: revisiting the pro-inflammatory paradigm.

Wanda Grabon, Nadia Gasmi, Anatole Lang, Anne Ruiz, Béatrice Georges, Victor Blot, Michaël Ogier, Sylvain Rheims, Fabrice P Navarro, Laurent Bezin.

  Neuroinflammation is central to temporal lobe epilepsy, yet the specific role of myeloid cells remains unclear. In status epilepticus (SE) models, circulating monocytes infiltrate the brain, although distinguishing them from microglia is challenging. Using a rat model, we traced infiltrating monocytes post-SE to investigate their persistence, phenotypic evolution during epileptogenesis and contribution to neuroinflammation. By tracking phagocytosed fluorescent nanoparticles and performing CD68 immunohistochemistry, we confirmed that monocytes entered the brain in significant numbers 24 hours post-SE, after the inflammatory peak occurred (7 hours). Their long-term presence and evolution into monocyte-macrophages (mo-mΦs) up to 7 weeks were monitored histologically using CD68. Distinct inflammatory profiles were further characterized after cell enrichment and fluorescence-activated cell sorting (FACS) distinguishing monocytes/mo-mΦs (CD11b+CD45hiCD11ahi) from microglia (CD11b+CD45loCD11alo). Microglia were the main drivers of the early pro-inflammatory response, with TNFα transcript levels nearly 14-fold higher in microglia than in monocytes 24h post-SE. In contrast, 24h post-SE, infiltrating monocytes transiently displayed an anti-inflammatory and neuroprotective phenotype, being the main source of IL-10, showing ~4-fold higher CD206, and expressing Arg1 absent in microglia. Tracked up to 7 weeks, these cells progressively adopted a microglia-like phenotype, contributed to the microglial scar and, although their expression of pro-inflammatory markers resembled nonactivated microglia, we hypothesize that their persistent presence might fuel the low-grade inflammation typical of chronic epilepsy. Importantly, since infiltrating monocytes initially engage in a transient anti-inflammatory response, strategies aiming to sustain or enhance this protective role in the context of epileptogenesis and epilepsy may open promising avenues for therapeutic intervention.

Keywords:  brain cell sorting; infiltrating monocytes; microglia; neuroinflammation; temporal lobe epilepsy

DOI:  https://doi.org/10.3389/fimmu.2025.1695856
Cell Signal. 2025 Dec 18. pii: S0898-6568(25)00751-X. [Epub ahead of print]139 112336

ANXA1 regulates microglia polarization and autophagy via PI3K/Akt/mTOR pathway to reduce inflammatory injury after cerebral ischemia-reperfusion.

Hua Wang, Xiaohui Li, Ziyu Liu, Ruirui Lu, Xiaopeng Li, Xiaoguang Zhang.

   BACKGROUND: Annexin A1 (ANXA1) can be activated by ischemia/reperfusion (I/R) events or inflammatory processes, but its specific regulatory mechanisms need further investigation.
METHODS: ANXA1 in BV-2 cells was knocked down or overexpressed, and OGD/R induced injury, while 740YP and LY294002 were used for intervention. Microglia polarization phenotype and marker levels were assessed through flow cytometry, RT-qPCR and western blot. Autophagic flux and lysosomal function were evaluated by mCherry-GFP-LC3B, acridine orange (AO) staining and LysoTracker staining. ANXA1 and PI3K/Akt/mTOR proteins were detected by western blot. The tMCAO/R mouse model was established. Longa score, behavioral test and pathological staining to assess the extent of nerve injury, and microglia polarization and autophagy indicators were detected.
RESULTS: ANXA1 expression was decreased in OGD/R-treated microglia. ANXA1 overexpression facilitated the transformation of microglia phenotype from M1-like phenotype to M2-like phenotype, increased CD206 and IL-10 expression, reduced the GFP/mCherry ratio and LysoTracker positive cells, and increased the red fluorescence of AO staining. ANXA1 overexpression also significantly reduced PI3K, Akt and mTOR phosphorylation. Moreover, ANXA1 overexpression markedly decreased Longa score, brain water content and infarct size, improved motor and neurological impairment in tMCAO/R mice, elevated Nissl bodies and Iba-1+CD206+ positive area, and reduced necrotic neuron numbers, inflammatory factor content and autophagy protein levels. In addition, 740YP significantly inhibited the improvement of ANXA1 overexpression, and LY294002 significantly enhanced the improvement of ANXA1 overexpression.
CONCLUSION: Overexpression of ANXA1 regulated microglia polarization and autophagic flux via regulating PI3K/Akt/mTOR pathway, and improved cerebral I/R inflammatory injury.

Keywords:  ANXA1; Autophagy; Microglia; PI3K/Akt/mTOR signaling; Polarization

DOI:  https://doi.org/10.1016/j.cellsig.2025.112336
Neurosci Lett. 2025 Dec 19. pii: S0304-3940(25)00382-9. [Epub ahead of print]873 138493

Chlorogenic acid exerts anti-inflammation and neuroprotective effect in pentylenetetrazole-induced epilepsy mouse model by regulating microglia polarization via Nrf2/HO-1 pathway.

Yi Sun, Jiayu Wang, Aoyuan Zhang, Ankang Hu, Lianlian Wu.

  Chlorogenic acid (CGA) possesses diverse biological functions, including antioxidant, anti-inflammatory, and anti-apoptotic, both in vitro and in vivo. Recent studies have suggested that CGA also has neuroprotective effects. However, its potential to alleviate seizures and attenuate epilepsy-related neuropathology remains unclear. This study investigated the effects and underlying mechanisms of CGA in a pentylenetetrazole (PTZ)-induced epilepsy mouse model. CGA treatment significantly reduced epileptic seizures. Nissl and NeuN immunofluorescence staining revealed that CGA also significantly reduced neuronal damage. Furthermore, CGA promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype and suppressed neuroinflammation, evidenced by iNOS/IBA-1 and Arg-1/IBA-1 immunofluorescence and RT-PCR. BrdU staining revealed that CGA inhibited epilepsy-induced aberrant neurogenesis. In addition, behavioral tests showed improved cognitive performance following CGA treatment. Finally, western blot analysis indicated the activation of the Nrf2/HO-1 pathway, and Nrf2 knockdown reversed CGA's effects. These findings suggest that CGA exerts anti-seizure and neuroprotective effects via microglial modulation through the Nrf2/HO-1 pathway.

Keywords:  Chlorogenic acid; Epileptic; Microglia; Neuroinflammation; Pentylenetetrazole

DOI:  https://doi.org/10.1016/j.neulet.2025.138493
Biol Sex Differ. 2025 Dec 24.

Sex-dependent immune activation shapes disease progression in a model of Parkinson's disease.

Leah C Beauchamp, Lily A Palumbo, Toby B Lanser, Mariam Baig, Laura M Cox.

   BACKGROUND: While it is clear that inflammation contributes to Parkinson's disease (PD) and prevalence is higher in males, sex remains an underexplored determinant of immune responses in PD.
METHODS: Using the 3KL transgenic mouse model, which expresses three E to K α-synuclein mutations, we investigated how sex and age shape peripheral and central immunity and behavior in synucleinopathy. Male and female 3KL mice were aged to 8- and 14-months. At these ages animals underwent motor and cognitive assessment, followed by assessment of the peripheral immune response using flow cytometry and analysis of microglial transcriptional profiles by bulk RNA sequencing.
RESULTS: Male 3KL mice exhibited earlier onset and greater severity of motor and cognitive impairments, which was linked to a pro-inflammatory peripheral immune profile marked by increased cytotoxic CD8⁺ T cells and IFNγ-producing CD4 Th1 cells. In contrast, female mice displayed delayed symptom onset, preserved cognition, along with early elevations in regulatory IL-10⁺ CD4 and γδ T cells. RNA sequencing of microglia revealed broad sex differences at 8 months. Males demonstrated early upregulation of microglia neurodegenerative signatures, MHC class I/II signaling, ceramide signaling, and pronounced lipid dysregulation, while females showed upregulation of microglial pathways related to protein, metabolic, and neuronal maintenance, including phagosome formation, docosahexaenoic acid signaling, and synaptogenesis pathways. Microglial transcriptional differences were nearly absent by 14 months, suggesting sex-specific trajectories converge during late-stage disease, which is concurrent with a decrease in estrogen in aged female mice.
CONCLUSIONS: Together, these findings reveal distinct immune signaling in male and female 3KL mice and identify coordinated changes in T cell and microglial responses that may contribute to sex differences in PD vulnerability and progression. This work underscores the importance of incorporating sex as a biological variable in neurodegeneration research and provides mechanistic insight into immune-mediated modulation of synucleinopathy.

Keywords:  3KL; Aging; Alpha synuclein; Cognition; Microglia; Parkinson’s disease; Sex; T cells

DOI:  https://doi.org/10.1186/s13293-025-00809-1
Adv Sci (Weinh). 2025 Dec 22. e13400

Flipping the Switch: MeCP2-Mediated Lactylation Rewires Microglial Metabolism and Inflammation via the HK2/mTOR Axis in Poststroke Neuroinflammation.

Zengyu Zhang, Shanshan Huang, Yong Wang, Zhiwen Jiang, Zhuohang Liu, Chenran Wang, Rong Ji, Yiwen Yuan, Xueyu Mao, Kaicheng Yang, Huicong Niu, Yanqin Gao, Jing Zhao.

  Microglial metabolic/inflammatory reprogramming critically influences stroke outcomes, yet its mechanisms remain poorly understood. Lysine lactylation, an epigenetic modification in which lactate-derived lactyl groups modify lysine residues, regulates immune and neurological processes. Here, lysine lactylation is identified as a key link between ischemic metabolic stress and microglial dysfunction. Stroke-induced lactate accumulation drives microglial protein lactylation, which correlates with poor neurological outcomes. Proteomics identified that methyl-CpG binding protein 2 (MeCP2) is lactylated at lysine 210 (K210), enhancing its transcriptional activation of glycolytic/inflammatory genes, especially hexokinase 2 (HK2). HK2 overexpression mimics lactylation-induced pathology (mitochondrial dysfunction, glycolytic shift, inflammation), while knockdown reverses these effects. Lactylated MeCP2 impairs mitochondrial respiration, disrupts metabolic signaling (leading to dysregulated activation of the mammalian target of rapamycin (mTOR)/AMPK pathway), and sustains neuroinflammation. Genetic ablation of MeCP2-K210 lactylation (via K210R mutation), pharmacological inhibition of lactyltransferase p300, or HK2 inhibition with lonidamine restores mitochondrial function, attenuates neuroinflammation, and improves neurofunctional recovery. The findings establish MeCP2-K210 lactylation as a critical metabolic-epigenetic switch driving microglial activation via the HK2/mTOR axis, identifying a therapeutic target for postischemic neuroinflammation.

Keywords:  MeCP2; ischemic stroke; lactylation; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/advs.202513400
Exp Biol Med (Maywood). 2025 ;250 10808

Mapping microglial mechanisms in Alzheimer's disease: a comprehensive analysis.

Xiaofang Wang, Yuqing Guo, Yonghan Zha, Shuling Wang, Weihua Yang, Qianfang Jia.

  Microglia, the brain's primary immune cells, play crucial roles in Alzheimer's disease (AD) pathogenesis. However, existing research remains abundant yet fragmented. Therefore, this study aimed to systematically identify hotspots and trends in microglia-related AD research, while providing an in-depth analysis of the underlying mechanisms to advance mechanistic understanding and therapeutic development. To achieve this, articles on microglia in AD were retrieved from the Web of Science Core Collection (WoSCC) database, and bibliometric analysis was performed using the WoSCC platform and CiteSpace 6.3.R1, with a focus on global collaboration, institutional and journal contributions, keyword bursts, and high-impact articles to comprehensively elucidate the underlying mechanisms. In total, 1,043 articles from 67 countries and regions were included.Among them, the United States led with 484 articles and an H-index of 100, followed by China with 276 articles. The University of California system (77 articles) and Harvard University (74 articles) had the highest H-index, both at 41. Journal of Neuroinflammation published the most articles (57 articles). Burst keywords persisting until 2024 included "memory," "NLRP3 inflammasome," and "system." High-impact studies emphasized microglial roles in AD pathology, including Aβ clearance, synaptic pruning, inflammation, metabolism, phenotype shifts, immune memory, and genetic variation. Overall, microglial mechanisms are at the forefront of AD research. The United States leads in both article number and influence, followed by China. The University of California system and Harvard University demonstrate the greatest output and impact. Journal of Neuroinflammation is the leading journal. Microglial NLRP3 activation, system-level interactions, and memory impairment have emerged as key research hotspots in AD. Future research will focus on microglial mechanisms and therapeutic targets in AD.

Keywords:  Alzheimer’s disease; hotspot; mechanism; microglia; trend

DOI:  https://doi.org/10.3389/ebm.2025.10808