bims-microg 2025-01-19 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–01–19
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln

Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.
Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.
TREM2 affects DAM-like cell transformation in the acute phase of TBI in mice by regulating microglial glycolysis.
Satellite microglia: marker of traumatic brain injury and regulator of neuronal excitability.
Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease.
Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis.
Lipid droplets in central nervous system and functional profiles of brain cells containing lipid droplets in various diseases.
Genome-wide and phenome-wide studies provided insights into brain glymphatic system function and its clinical associations.
A Comprehensive Analysis of Sex-Biased Gene Expression in the Aging Human Retina Through a Combination of Single-Cell and Bulk RNA Sequencing.
Myelin debris as an initiator of microglial dysfunction and neuropathology in Alzheimer's disease.
The Role of Fractalkine in Diabetic Retinopathy: Pathophysiology and Clinical Implications.
Association between choroidal microvasculature in the eye and Alzheimer's disease risk in cognitively healthy mid-life adults: A pilot study.
Infiltrating peripheral monocyte TREM-1 mediates dopaminergic neuron injury in substantia nigra of Parkinson's disease model mice.
DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.
Neurons as Immunomodulators: From Rapid Neural Activity to Prolonged Regulation of Cytokines and Microglia.
Ferroptosis-related genes participate in the microglia-induced neuroinflammation of spinal cord injury via NF-κB signaling: evidence from integrated single-cell and spatial transcriptomic analysis.
PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signal.
The opposite effect of ELP4 and ZEB2 on TCF7L2-mediated microglia polarization in ischemic stroke.
TBC1D15 Inhibits Autophagy of Microglia through Maintaining the Damaged Swelling Lysosome in Alzheimer's Disease.

Cell Rep. 2025 Jan 14. pii: S2211-1247(24)01555-9. [Epub ahead of print]44(1): 115204

Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.

Leigh Ellen Fremuth, Huimin Hu, Diantha van de Vlekkert, Ida Annunziata, Jason Andrew Weesner, Alessandra d'Azzo.

  Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.

Keywords:  Alzheimer disease; CP: Immunology; CP: Neuroscience; Trem2; microglia; neuraminidase 1; neurodegeneration; neuroinflammation; sialidosis; sialylation

DOI:  https://doi.org/10.1016/j.celrep.2024.115204
Sci Transl Med. 2025 Jan 15. 17(781): eadk3690

Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.

Wesley Brandao, Nimansha Jain, Zhuoran Yin, Kilian L Kleemann, Madison Carpenter, Xin Bao, Javier R Serrano, Eric Tycksen, Ana Durao, Jen-Li Barry, Caroline Baufeld, Dilansu Guneykaya, Xiaoming Zhang, Alexandra Litvinchuk, Hong Jiang, Neta Rosenzweig, Kristen M Pitts, Michael Aronchik, Taha Yahya, Tian Cao, Marcelo Kenzo Takahashi, Rajesh Krishnan, Hayk Davtyan, Jason D Ulrich, Mathew Blurton-Jones, Ilya Ilin, Howard L Weiner, David M Holtzman, Oleg Butovsky.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.

DOI: https://doi.org/10.1126/scitranslmed.adk3690
J Neuroinflammation. 2025 Jan 13. 22(1): 6

TREM2 affects DAM-like cell transformation in the acute phase of TBI in mice by regulating microglial glycolysis.

Lin Wang, Diqing Ouyang, Lin Li, Yunchuan Cao, Yingwen Wang, Nina Gu, Zhaosi Zhang, Zhao Li, Shuang Tang, Hui Tang, Yuan Zhang, Xiaochuan Sun, Jin Yan.

   BACKGROUND: Traumatic brain injury (TBI) is characterized by high mortality and disability rates. Disease-associated microglia (DAM) are a newly discovered subtype of microglia. However, their presence and function in the acute phase of TBI remain unclear. Although glycolysis is important for microglial differentiation, its regulatory role in DAM transformation during the acute phase of TBI is still unclear. In this study, we investigated the functions of DAM-like cells in the acute phase of TBI in mice, as well as the relationship between their transformation and glycolysis.
METHODS: In this study, a controlled cortical impact model was used to induce TBI in adult male wild-type (WT) C57BL/6 mice and adult male TREM2 knockout mice. Various techniques were used to assess the role of DAM-like cells in TBI and the effects of glycolysis on DAM-like cells, including RT‒qPCR, immunofluorescence assays, behavioural tests, extracellular acidification rate (ECAR) tests, Western blot analysis, cell magnetic sorting and culture, glucose and lactate assays, and flow cytometry.
RESULTS: DAM-like cells were observed in the acute phase of TBI in mice, and their transformation depended on TREM2 expression. TREM2 knockout impaired neurological recovery in TBI mice, possibly due in part to their role in clearing debris and secreting VEGFa and BDNF. Moreover, DAM-like cells exhibited significantly increased glycolytic activity. TREM2 regulated the AKT‒mTOR‒HIF-1α pathway and glycolysis in microglia in the acute phase of TBI. The increase in glycolysis in microglia partially contributed to the transformation of DAM-like cells in the acute phase of TBI in mice.
CONCLUSIONS: Taken together, the results of our study demonstrated that DAM-like cells were present in the acute phase of TBI in mice. TREM2 might influence DAM-like cell transformation by modulating the glycolysis of microglia. Our results provide a new possible pathway for intervening TBI.

Keywords:  Disease-associated microglia; Glycolysis; Microglia; Traumatic brain injury; Triggering receptor expressed on myeloid cells 2

DOI:  https://doi.org/10.1186/s12974-025-03337-2
J Neuroinflammation. 2025 Jan 16. 22(1): 9

Satellite microglia: marker of traumatic brain injury and regulator of neuronal excitability.

Alicia B Feichtenbiner, Karinn Sytsma, Ryan P O'Boyle, Rhonda Mittenzwei, Heather Maioli, Kathryn P Scherpelz, Daniel D Child, Ning Li, Jeanelle Ariza Torres, Lisa Keene, Amanda Kirkland, Kimberly Howard, Caitlin Latimer, C Dirk Keene, Christopher Ransom, Amber L Nolan.

  Traumatic brain injury is a leading cause of chronic neurologic disability and a risk factor for development of neurodegenerative disease. However, little is known regarding the pathophysiology of human traumatic brain injury, especially in the window after acute injury and the later life development of progressive neurodegenerative disease. Given the proposed mechanisms of toxic protein production and neuroinflammation as possible initiators or contributors to progressive pathology, we examined phosphorylated tau accumulation, microgliosis and astrogliosis using immunostaining in the orbitofrontal cortex, a region often vulnerable across traumatic brain injury exposures, in an age and sex-matched cohort of community traumatic brain injury including both mild and severe cases in midlife. We found that microglial response is most prominent after chronic traumatic brain injury, and interactions with neurons in the form of satellite microglia are increased, even after mild traumatic brain injury. Taking our investigation into a mouse model, we identified that these satellite microglia suppress neuronal excitability in control conditions but lose this ability with chronic traumatic brain injury. At the same time, network hyperexcitability is present in both mouse and human orbitofrontal cortex. Our findings support a role for loss of homeostatic control by satellite microglia in the maladaptive circuit changes that occur after traumatic brain injury.

Keywords:  Cortical circuits; Electrophysiology; Microglia; Neuropathology; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12974-024-03328-9
EMBO Mol Med. 2025 Jan 10.

Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease.

Davina Biel, Marc Suárez-Calvet, Anna Dewenter, Anna Steward, Sebastian N Roemer, Amir Dehsarvi, Zeyu Zhu, Julia Pescoller, Lukas Frontzkowski, Annika Kreuzer, Christian Haass, Michael Schöll, Matthias Brendel, Nicolai Franzmeier.

  In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau181. To determine effects of microglial activation on p-tau181, we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau181 levels. Higher sTREM2 was associated with elevated p-tau181, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau181 levels and faster p-tau181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women.

Keywords:  Alzheimer’s Disease; Microglia; Sex Differences; p-tau; sTREM2

DOI:  https://doi.org/10.1038/s44321-024-00190-3
Cell Rep. 2025 Jan 15. pii: S2211-1247(24)01545-6. [Epub ahead of print]44(1): 115194

Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis.

Ashleigh Willis, Danielle Jeong, Yunlong Liu, Marissa A Lithopoulos, Scott A Yuzwa, Paul W Frankland, David R Kaplan, Freda D Miller.

  Here, we used single cell RNA sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We defined the dorsal and lateral ventricular-subventricular zones (V-SVZs) as two distinct neighborhoods and showed that, after white matter injury, NSCs are activated to make oligodendrocytes dorsally for remyelination. This activation is coincident with an increase in transcriptionally distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, insulin growth factor 1 and oncostatin M, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.

Keywords:  CP: Neuroscience; CP: Stem cell research; insulin-like growth factor 1; microglia; myelin; neural stem cells; oligodendrogenesis; oncostatin M; remyelination; scRNA-seq; single cell spatial transcriptomics; white matter injury

DOI:  https://doi.org/10.1016/j.celrep.2024.115194
J Neuroinflammation. 2025 Jan 13. 22(1): 7

Lipid droplets in central nervous system and functional profiles of brain cells containing lipid droplets in various diseases.

Longxiao Zhang, Yunfei Zhou, Zhongbo Yang, Liangchao Jiang, Xinyang Yan, Wenkai Zhu, Yi Shen, Bolong Wang, Jiaxi Li, Jinning Song.

  Lipid droplets (LDs), serving as the convergence point of energy metabolism and multiple signaling pathways, have garnered increasing attention in recent years. Different cell types within the central nervous system (CNS) can regulate energy metabolism to generate or degrade LDs in response to diverse pathological stimuli. This article provides a comprehensive review on the composition of LDs in CNS, their generation and degradation processes, their interaction mechanisms with mitochondria, the distribution among different cell types, and the roles played by these cells-particularly microglia and astrocytes-in various prevalent neurological disorders. Additionally, we also emphasize the paradoxical role of LDs in post-cerebral ischemia inflammation and explore potential underlying mechanisms, aiming to identify novel therapeutic targets for this disease.

Keywords:  Inflammation; Lipid droplet; Lipid metabolism; Stress; Stroke

DOI:  https://doi.org/10.1186/s12974-025-03334-5
Sci Adv. 2025 Jan 17. 11(3): eadr4606

Genome-wide and phenome-wide studies provided insights into brain glymphatic system function and its clinical associations.

Lusen Ran, Yuanyuan Fang, Chang Cheng, Yuqin He, Zhonghe Shao, Yifan Kong, Hao Huang, Shabei Xu, Xiang Luo, Wei Wang, Xingjie Hao, Minghuan Wang.

We applied an MRI technique diffusion tensor imaging along the perivascular space (DTI-ALPS) for assessing glymphatic system (GS) in a genome-wide association study (GWAS) and phenome-wide association study (PheWAS) of 40,486 European individuals. Exploratory analysis revealed 17 genetic loci significantly associating with the regional DTI-ALPS index. We found 58 genes, including SPPL2C and EFCAB5, which prioritized in the DTI-ALPS index subtypes and associated with neurodegenerative diseases. PheWAS of 241 traits suggested that body mass index and blood pressure phenotypes closely related to GS function. Moreover, we detected disrupted GS function in 44 of 625 predefined disease conditions. Notably, Mendelian randomization and mediation analysis indicated that lower DTI-ALPS index was a risk factor for ischemic stroke (odds ratio = 1.56, P = 0.028) by partly mediating the risk factor of obesity. Results provide insights into the genetic architecture and mechanism for the DIT-ALPS index and highlight its great clinical value, especially in cerebral stroke.

DOI: https://doi.org/10.1126/sciadv.adr4606
Invest Ophthalmol Vis Sci. 2025 Jan 02. 66(1): 28

A Comprehensive Analysis of Sex-Biased Gene Expression in the Aging Human Retina Through a Combination of Single-Cell and Bulk RNA Sequencing.

Hongling Liu, Xue Zhang, Qing Wang, Bowen Li, Baishijiao Bian, Yong Liu.

Purpose: Previous studies have reported divergent sexual responses to aging; however, specific variations in gene expression between aging males and females and their potential association with age-related retinal diseases remain unclear. This study collected data from public databases and developed a comprehensive comparison of retina between aging females and males.
Methods: Single-cell RNA (scRNA) and bulk RNA sequencing data of the aging retina from females and males in public databases were utilized for integrated analysis to investigate sex-biased expression in retina. Additionally, in vitro experiments were conducted on individuals with retinitis pigmentosa (RP) to validate the sex difference in degenerative retina.
Results: Bulk RNA analysis revealed sex-biased expression of specific genes in retina of aging individuals, with immune pathway-related genes exhibiting higher expression in females compared to males. The scRNA analysis demonstrated that sex-biased gene expression was cell-type specific in aging retina. Furthermore, susceptibility genes for age-related macular degeneration and RP exhibited variation across different cell types and sexes. Cell-to-cell communication unveiled an increased interaction associated with TGFB1, CCL7, and VEGFA in Müller glia, microglia, and astrocytes of female retina. Notably, we observed female-biased chemokine expression in microglia contributing to heightened susceptibility to immune inflammation in female retina. Finally, we confirmed a more pronounced inflammatory response during degeneration in female rd10 mouse retina compared to males.
Conclusions: This study provides a comprehensive comparison of retina between females and males in healthy aging human retina and highlights the significance of sex as an influential factor in retinal diseases.

DOI: https://doi.org/10.1167/iovs.66.1.28
Cell Mol Immunol. 2025 Jan 14.

Myelin debris as an initiator of microglial dysfunction and neuropathology in Alzheimer's disease.

Joshua D Samuels, John R Lukens.

DOI: https://doi.org/10.1038/s41423-024-01243-w
Int J Mol Sci. 2025 Jan 04. pii: 378. [Epub ahead of print]26(1):

The Role of Fractalkine in Diabetic Retinopathy: Pathophysiology and Clinical Implications.

Cheng-Yung Lee, Chang-Hao Yang.

  Diabetic retinopathy (DR) is a complication of diabetes, characterized by progressive microvascular dysfunction that can result in vision loss. Chronic hyperglycemia drives oxidative stress, endothelial dysfunction, and inflammation, leading to retinal damage and complications such as neovascularization. Current treatments, including anti-VEGF agents, have limitations, necessitating the exploration of alternative therapeutic strategies. Fractalkine (CX3CL1), a chemokine with dual roles as a membrane-bound adhesion molecule and a soluble chemoattractant, has emerged as a potential therapeutic target. Its receptor, CX3CR1, is expressed on immune cells and mediates processes such as immune cell recruitment and microglial activation through intracellular signaling pathways. In DR, soluble fractalkine plays critical roles in retinal inflammation, angiogenesis, and neuroprotection, balancing tissue damage and repair. In DR, elevated fractalkine levels are associated with retinal inflammation and endothelial dysfunction. Experimental studies suggest that fractalkine deficiency exacerbates the severity of diabetic retinopathy (DR), whereas exogenous fractalkine appears to reduce inflammation, oxidative stress, and neuronal damage. However, its role in pathological angiogenesis within DR remains unclear and warrants further investigation. Preclinical evidence indicates that fractalkine may hold therapeutic potential, particularly in mitigating tissue injury and inflammation associated with early-stage DR.

Keywords:  CX3CL1-CX3CR1 signaling; chemokine; diabetic retinopathy; fractalkine; fractalkine receptor; inflammation; microglia; soluble fractalkine; transmembrane fractalkine

DOI:  https://doi.org/10.3390/ijms26010378
Alzheimers Dement (Amst). 2025 Jan-Mar;17(1):17(1): e70075

Association between choroidal microvasculature in the eye and Alzheimer's disease risk in cognitively healthy mid-life adults: A pilot study.

Jamie Burke, Samuel Gibbon, Audrey Low, Charlene Hamid, Megan Reid-Schachter, Graciela Muniz-Terrera, Craig W Ritchie, Baljean Dhillon, John T O'Brien, Stuart King, Ian J C MacCormick, Thomas J MacGillivray.

   INTRODUCTION: We explored associations between measurements of the ocular choroid microvasculature and Alzheimer's disease (AD) risk.
METHODS: We measured the choroidal vasculature appearing in optical coherence tomography (OCT) scans of 69 healthy, mid-life individuals in the PREVENT Dementia cohort. The cohort was prospectively split into low-, medium-, and high-risk groups based on the presence of known risk factors (apolipoprotein E [APOE] ε4 genotype and family history of dementia [FH]). We used ordinal logistic regression to test for cross-sectional associations between choroidal measurements and AD risk.
RESULTS: Choroidal vasculature was progressively larger between ordinal risk groups, and significantly associated with risk group prediction. APOE ε4 carriers had thicker choroids and larger vascularity compared to non-carriers. Similar trends were observed for those with a FH.
DISCUSSIONS: Our results suggest a potential link between the choroidal vasculature and AD risk. However, these exploratory findings should be replicated in a larger sample.
Highlights: Ocular choroidal microvasculature is of interest in relation to neurodegeneration due to its autonomic response to systemic, pathophysiological change.Choroidal changes in the prodromal stage of Alzheimer's disease (AD) are unexplored.The PREVENT Dementia cohort offers a unique, non-invasive study of the microvasculature in mid-life individuals at increased risk for developing AD.Significantly increased ocular choroidal vasculature was associated with increased risk (apolipoprotein E carrier and/or family history of dementia) for AD.These exploratory results suggest a potential association between the ocular choroidal vasculature and AD risk. However, findings should be replicated in a larger sample.

Keywords:  apolipoprotein E ε4; choroid; dementia; optical coherence tomography; retina

DOI:  https://doi.org/10.1002/dad2.70075
Cell Death Dis. 2025 Jan 14. 16(1): 18

Infiltrating peripheral monocyte TREM-1 mediates dopaminergic neuron injury in substantia nigra of Parkinson's disease model mice.

Wei Song, Zi-Ming Zhou, Le-le Zhang, Hai-Feng Shu, Jin-Ru Xia, Xia Qin, Rong Hua, Yong-Mei Zhang.

Neuroinflammation is a key factor in the pathogenesis of Parkinson's disease (PD). Activated microglia in the central nervous system (CNS) and infiltration of peripheral immune cells contribute to dopaminergic neuron loss. However, the role of peripheral immune responses, particularly triggering receptor expressed on myeloid cells-1 (TREM-1), in PD remains unclear. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD mouse model, we examined TREM-1 expression and monocyte infiltration in the substantia nigra pars compacta (SNpc). We found that MPTP increased peripheral monocytes, and deletion of peripheral monocytes protected against MPTP neurotoxicity in the SNpc. TREM-1 inhibition, both genetically and pharmacologically, reduced monocyte infiltration, alleviated neuroinflammation, and preserved dopaminergic neurons, resulting in improved motor function. Furthermore, adoptive transfer of TREM-1-expressing monocytes from PD model mice to naive mice induced neuronal damage and motor deficits. These results underscore the critical role of peripheral monocytes and TREM-1 in PD progression, suggesting that targeting TREM-1 could be a promising therapeutic approach to prevent dopaminergic neurodegeneration and motor dysfunction in PD. Schematic diagram of monocyte TREM-1-mediated dopaminergic neuron damage. The figure illustrates that in experimental MPTP-induced PD model mice, the number of inflammatory monocytes in the peripheral blood increases, after which the monocytes infiltrate the CNS through the Blood-Brain Barrier(BBB). These infiltrating monocytes increase the release of inflammatory cytokines and eventually cause neuronal injury. TREM-1 gene deletion and pharmacological blockade limit inflammatory monocyte recruitment into the SNpc and ameliorate neuroinflammatory events and the loss of dopaminergic neurons.

DOI: https://doi.org/10.1038/s41419-025-07333-5
Nutrients. 2024 Dec 31. pii: 149. [Epub ahead of print]17(1):

DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.

Valentina Gentili, Giovanna Schiuma, Latha Nagamani Dilliraj, Silvia Beltrami, Sabrina Rizzo, Djidjell Lara, Pier Paolo Giovannini, Matteo Marti, Daria Bortolotti, Claudio Trapella, Marco Narducci, Roberta Rizzo.

   BACKGROUND: A neuroinflammatory disease such as Alzheimer's disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways.
METHODS: We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound's effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates.
RESULTS: DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation.
CONCLUSIONS: In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression.

Keywords:  Alzheimer’s disease; DAG-MAG-ΒHB; blood–brain barrier; exogenous ketones; ketone diester; neuroprotection; therapeutic ketosis

DOI:  https://doi.org/10.3390/nu17010149
Annu Rev Biomed Eng. 2025 Jan 13.

Neurons as Immunomodulators: From Rapid Neural Activity to Prolonged Regulation of Cytokines and Microglia.

Levi B Wood, Annabelle C Singer.

Regulation of the brain's neuroimmune system is central to development, normal function, and disease. Neuronal communication to microglia, the primary immune cells of the brain, is well known to involve purinergic signaling mediated via ATP secretion and the cytokine fractalkine. Recent evidence shows that neurons release multiple cytokines beyond fractalkine, yet these are less studied and poorly understood. In contrast to ATP, cytokines are a class of signaling molecule that are much larger, with longer signaling and farther diffusion. We posit that neuron-expressed cytokines are an essential mechanism of neuron-microglia communication that arises as part of both normal learning and memory and in response to tissue pathology. Thus, neurons are underappreciated immunomodulatory cells that express diverse immunomodulatory signals. While neuronally sourced cytokines have been understudied, new technical advances make this a timely topic. The goal of this review is to define what is known about the cytokines expressed from neurons, how they are regulated, and the effects of these cytokines on microglia. We delineate key knowledge gaps and needs for new tools to define and analyze neuronal roles in immunomodulation. Given that cytokines are central regulators of microglial function, a broad new body of work is required to illuminate functional links between these neuronally expressed cytokines and sustained and transient microglial function.

DOI: https://doi.org/10.1146/annurev-bioeng-110122-120158
J Transl Med. 2025 Jan 11. 23(1): 43

Ferroptosis-related genes participate in the microglia-induced neuroinflammation of spinal cord injury via NF-κB signaling: evidence from integrated single-cell and spatial transcriptomic analysis.

Siqiao Wang, Li Yang, Zhourui Wu, Chen Li, Shaoke Wang, Zhihui Xiao, Bei Ma, Rongrong Zhu, Liming Cheng.

   BACKGROUND: Ferroptosis and immune responses are critical pathological events in spinal cord injury (SCI), whereas relative molecular and cellular mechanisms remain unclear.
METHODS: Micro-array datasets (GSE45006, GSE69334), RNA sequencing (RNA-seq) dataset (GSE151371), spatial transcriptome datasets (GSE214349, GSE184369), and single cell RNA sequencing (scRNA-seq) datasets (GSE162610, GSE226286) were available from the Gene Expression Omnibus (GEO) database. Through weighted gene co-expression network analysis and differential expression analysis in GSE45006, we identified differentially expressed time- and immune-related genes (DETIRGs) associated with chronic SCI and differentially expressed ferroptosis- and immune-related genes (DEFIRGs), which were validated in GSE151371. Protein-protein interaction and microRNA-mRNA-transcription factor regulatory networks were constructed based on Search Tool for the Retrieval of Interacting Genes (STRING) and NetworkAnalyst, respectively, which were validated by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Cell subclusters and unique features of microglia in SCI were identified by single-cell transcriptomic analysis, which were validated in GSE226286. Spatial expression patterns of DETIRGs and DEFIRGs were validated in brain injury (GSE214349) and SCI (GSE184369). Potential mechanisms underlying neuronal regeneration by neurotrophin-3 (NT3)-chitosan were revealed by transcriptomic analyses in GSE69334. Immune- and ferroptosis-related mechanisms of nanolayered double hydroxide loaded with NT3 (LDH-NT3) were investigated in vivo and in vitro.
RESULTS: GBP2, TEC, UNC93B1, PLXNC1, NFATC1, IL10RB, and TLR8 were DETIRGs represented chronic SCI-specific genes and peripheral blood biomarkers. NFKB1 may regulate expression of CYBB and HMOX1 in a unique subcluster of M1 microglia within the middle SCI lesion, establishing links between microglial ferroptosis and neuroinflammation. Reduced inflammatory responses and microglial ferroptosis were potential effects of NT3-chitosan or LDH-NT3 on neuronal regeneration.
CONCLUSIONS: A novel subcluster of microglia exhibiting M1 polarization and ferroptosis phenotype was involved in SCI. These microglia may trigger neuroinflammation and induce neuronal degeneration within the middle site of SCI, which might be inhibited by NT3-chitosan or LDH-NT3.

Keywords:  Biomaterial; Ferroptosis; Immune responses; Microglia; Single-cell RNA sequencing; Spinal cord injury

DOI:  https://doi.org/10.1186/s12967-025-06095-0
Tissue Cell. 2025 Jan 14. pii: S0040-8166(25)00019-9. [Epub ahead of print]93 102739

PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signal.

Tao Su, Yuting Si.

   BACKGROUND: Postoperative cognitive dysfunction (POCD) is a postoperative complication that can be induced by anaesthesia. PCSK9 has been shown to have a role in neuronal development and apoptosis. However, PCSK9 has not been studied in sevoflurane-induced POCD-related disorders.
OBJECTIVE: To explore whether PCSK9 can exacerbate sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signalling.
METHODS: A POCD model was constructed by stimulating BV2 microglia with Sevoflurane. CCK8 was used to detect the cell viability, and immunofluorescence was used to observe the expression of microglial activation markers (Iba-1, CD11b) and BDNF to determine the activation of BV2 microglia. Cell proliferation was measured by EDU staining, and apoptosis was analyzed by flow cytometry and western blot. The levels of inflammatory cytokines, ROS, MDA, SOD and CAT were respectively detected by ELISA, DCFH-DA staining, and kits to determine the neuroinflammation and oxidative stress of cells. Mitochondrial ROS, mitochondrial membrane potential, mtDNA and ATP levels were measured to evaluate cellular mitochondrial function.
RESULTS: Transfection of si-PCSK9 inhibited Sevoflurane-induced microglial activation and restored cellular viability, promoted cell proliferation, inhibited apoptosis and neuroinflammation, decreased ROS and MDA levels in the cells while up-regulating the levels of SOD and CAT, thus inhibiting oxidative stress, restored the mitochondrial membrane potential to normal and decreased mitochondrial ROS and mtDNA levels and increased ATP production, thereby alleviating mitochondrial dysfunction. Moreover, PCSK9 depletion also down-regulated the expression of cGAS and STING to inactivate cGAS-STING signaling. However, cGAS overexpression partially reversed the effects of si-PCSK9.
CONCLUSION: PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by upregulating cGAS-STING signaling.

Keywords:  CGAS-STING; PCSK9; POCD; Sevoflurane

DOI:  https://doi.org/10.1016/j.tice.2025.102739
J Cell Commun Signal. 2025 Mar;19(1): e12061

The opposite effect of ELP4 and ZEB2 on TCF7L2-mediated microglia polarization in ischemic stroke.

Xiao-Li Min, Sixian Lin, Jia-Yi Hu, Rui Jing, Qing Zhao, Fei-Fei Shang, Yong Zeng.

  Microglia M1 polarization plays important role in the development of ischemic stroke (IS). This study explored the role of transcription factor 7 like 2 (TCF7L2) in regulating microglia M1 polarization during IS. TTC staining was used to determine the cerebral infarction, and Nissl staining was applied to examine neuronal injury. The secretion levels of cytokines were measured using ELISA. The interaction between Zinc finger E-Box binding homeobox 2 (ZEB2) and TCF7L2 was analyzed by Co-IP, and H3K27ac enrichment in the TCF7L2 promoter was detected by ChIP assay. TCF7L2 knockdown reduced MCAO/R-induced mice cerebral injury. TCF7L2 silencing or TAK-242 (TLR4 antagonist) injection inhibited OGD/R-induced microglia M1 polarization by repressing the TLR4/NF-κB signal, and TCF7L2 knockdown combined with TAK-242 treatment further inhibited microglia M1 polarization. TCF7L2 promoted transcriptional activation of TLR4. ELP4 enhanced H3K27ac-mediated transcriptional activation of TCF7L2, and ZEB2 promoted the K48-linked ubiquitination of TCF7L2. TCF7L2 overexpression abolished the inhibitory effect of ELP4 knockdown or ZEB2 overexpression on OGD/R-induced microglia M1 polarization. TCF7L2 exacerbated cerebral injury by promoting microglia M1 polarization during IS progression. Mechanistically, ELP4 promoted TCF7L2 expression by promoting H3K27ac enrichment in the TCF7L2 promoter, while ZEB2 promoted TCF7L2 ubiquitination degradation.

Keywords:  ELP4; TCF7L2; ZEB2; ischemic stroke; microglia M1 polarization

DOI:  https://doi.org/10.1002/ccs3.12061
Aging Dis. 2025 Jan 09.

TBC1D15 Inhibits Autophagy of Microglia through Maintaining the Damaged Swelling Lysosome in Alzheimer's Disease.

You Wu, Yong-Ming Zhou, Wei Wu, Wan-Rong Jiang, Xin-Yuan Zhang, Si-Yuan Song, Zhao-Hui Yao.

Autophagy in microglia is essential for the clearance of amyloid-beta (Aβ) and amyloid plaques in Alzheimer's disease. However, reports regarding the levels of autophagy in microglia have been inconsistent; some studies indicate an early enhancement followed by a subsequent reduction, while others describe a persistently weakened state. Notably, there is a lack of systematic studies documenting the temporal changes in microglial autophagy. TBC1D15, a Rab GTPase, plays a crucial role in lysosomal membrane repair, yet its function in regulating microglial autophagy in Alzheimer's disease remains unexplored. Current research suggests that microglial autophagy is activated in 3-month-old AD mice but gradually decreases by 12 months of age. Furthermore, TBC1D15 levels are significantly elevated in the lysosomes of microglia in Alzheimer's disease. Silencing TBC1D15 markedly inhibits swelling and Aβ phagocytosis in BV2 cells following Aβ treatment while simultaneously promoting autophagy and lysophagy. LIMP II/ATG8-TBC1D15-Dynamin2/RAB7 might participate in lysosome swelling of microglia in AD. These findings indicate that TBC1D15 in microglia is critical for the decline of autophagy in Alzheimer's disease. It is suggested that targeting microglial TBC1D15 may be an important strategy for enhancing autophagy, which facilitates the clearance of amyloid plaques as a therapeutic approach for Alzheimer's disease.

DOI: https://doi.org/10.14336/AD.2024.1373