bims-microg Biomed News
on Microglia in health and disease
Issue of 2025–01–26
twenty-one papers selected by
Marcus Karlstetter, Universität zu Köln



  1. Sci Rep. 2025 Jan 22. 15(1): 2867
      Excessive iron deposition can lead to ferroptosis, a form of iron-dependent cell death detrimental to neuronal survival. Microglia have been identified as having a high capacity for iron deposition, yet it remains unclear whether microglia undergo ferroptosis while phagocytosing excessive amounts of iron after spinal cord injury (SCI). Here, we observed scattered iron around the epicenter of the injured spinal cord at 7 days post-injury (dpi) in mice, which then accumulated in the lesion core at 14 dpi. Concurrently, microglia exhibited elevated expression of the iron-storage protein ferritin and were found to undergo ferroptosis between 7 and 28 dpi. Additionally, we noted a gradual decrease in glycosylated lysosomal membrane protein (GLMP) which is associated with iron metabolism in microglia undergoing ferroptosis. In situ injection of AAV9-Cx3cr1-shGlmp-eGFP to knock down GLMP specifically in microglia resulted in a significant increase in iron deposition and ferroptosis, leading to an expanded lesion area, aggravated neuronal loss, and subsequent inhibition of functional restoration. Our findings highlight the crucial role of GLMP in mitigating iron overload and ferroptosis in microglia, thereby contributing to axon retention and locomotor recovery after SCI.
    Keywords:  Ferroptosis; GLMP; Iron deposition; Microglia; Spinal cord injury
    DOI:  https://doi.org/10.1038/s41598-025-86991-z
  2. Cell Rep. 2025 Jan 09. pii: S2211-1247(24)01527-4. [Epub ahead of print] 115176
      Microglia, the resident macrophages of the brain, are derived from the yolk sac and colonize the brain before the blood-brain barrier forms. Once established, they expand locally and require Colony-stimulating-factor-1 receptor (CSF1R) signaling for their development and maintenance. CSF1R inhibitors have been used extensively to deplete microglia in the healthy and diseased brain. In this study, we demonstrated sex-dependent differences in the microglial response to the CSF1R inhibitor PLX3397. Male mice exhibited greater microglial depletion compared to females. Transcriptomic and flow cytometry analysis revealed sex-specific differences in the remaining microglia population, with female microglia upregulating autophagy and proteostasis pathways while male microglia increased mitobiogenesis. Furthermore, manipulating key microglial receptors by using different transgenic mouse lines resulted in changes in depletion efficacies that were also sex dependent. These findings suggest sex-dependent microglial survival mechanisms, which might contribute to the well-documented sex differences in various neurological disorders.
    Keywords:  CP: Immunology; CP: Neuroscience; Colony-stimulating-factor-1 receptor, TREM2, CX3C motif chemokine receptor 1, Galectin-3; PLX3397; microglia; sex-dependent differences; survival signaling
    DOI:  https://doi.org/10.1016/j.celrep.2024.115176
  3. Exp Eye Res. 2025 Jan 21. pii: S0014-4835(25)00017-X. [Epub ahead of print] 110246
      The P2X7 receptor (P2X7R) for extracellular ATP is implicated in several forms of retinal degeneration, including diabetic retinopathy, age-related macular degeneration, and glaucoma. P2X7R stimulation can trigger release of master cytokine IL-1β from microglia in the brain and from macrophages, but evidence of release from retinal microglia is indirect. Isolated mouse and rat retinal microglia, and wholemounts from CX3CR1+/GFP mice, were examined to determine if ATP induced IL-1β release directly from retinal microglial cells and if it also primed expression of IL-1β on an mRNA and protein level. Isolated retinal microglia were ramified and expressed low levels of polarization markers unless provoked. Over 90% of isolated microglial cells expressed P2X7R, with cytoplasmic Ca2+ elevation following receptor stimulation. ATP induced a dose-dependent release of IL-1β from primed microglial cells that was blocked by P2X7R antagonist A839977 and emulated by agonist BzATP. P2X7R stimulation also primed Il1b mRNA in isolated microglia cells. BzATP increased IL-1β immunostaining and GFP fluorescence throughout lamina of retinal wholemounts from CX3CR1+/GFP mice. Some of the IL-1β and GFP signals colocalized, particularly in the outer retina, and in projections extending distally through photoreceptor layers. The inner retina had more microglia without IL-1β, and more IL-1β staining without microglia. Substantial IL-1β release was also detected from rat retinal microglial cells, but not optic nerve head astrocytes. In summary, this study implicates microglial cells as a key source of released IL-1β when levels of extracellular ATP are increased following retinal damage, and suggest a greater participation in the outer retina.
    Keywords:  IL-1beta; NLRP3 inflammasome; Neuroinflammation; P2X7 receptor; age-dependent neurodegeneration; astrocyte; cytokine release; glaucoma; retinal microglia
    DOI:  https://doi.org/10.1016/j.exer.2025.110246
  4. Nat Neurosci. 2025 Jan 17.
      Microglia-resident immune cells in the central nervous system-undergo morphological and functional changes in response to signals from the local environment and mature into various homeostatic states. However, niche signals underlying microglial differentiation and maturation remain unknown. Here, we show that neuronal micronuclei (MN) transfer to microglia, which is followed by changing microglial characteristics during the postnatal period. Neurons passing through a dense region of the developing neocortex give rise to MN and release them into the extracellular space, before being incorporated into microglia and inducing morphological changes. Two-photon imaging analyses have revealed that microglia incorporating MN tend to slowly retract their processes. Loss of the cGAS gene alleviates effects on micronucleus-dependent morphological changes. Neuronal MN-harboring microglia also exhibit unique transcriptome signatures. These results demonstrate that neuronal MN serve as niche signals that transform microglia, and provide a potential mechanism for regulation of microglial characteristics in the early postnatal neocortex.
    DOI:  https://doi.org/10.1038/s41593-024-01863-5
  5. Glia. 2025 Jan 19.
      Microglia, the parenchymal macrophage of the central nervous system, serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX, Itgax, subunit of complement receptor 4) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is partially dependent upon the TAM receptor AXL. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest that CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.
    Keywords:  CD11c; development; microglia; neuronal apoptosis; phagocytosis
    DOI:  https://doi.org/10.1002/glia.24674
  6. J Physiol Sci. 2024 ;pii: S1880-6546(24)00121-5. [Epub ahead of print]74(1): 37
      An increase in ambient temperature leads to an increase in sleep. However, the mechanisms behind this phenomenon remain unknown. This study aimed to investigate the role of microglia in the increase of sleep caused by high ambient temperature. We confirmed that at 35 °C, slow-wave sleep was significantly increased relative to those observed at 25 °C. Notably, this effect was abolished upon treatment with PLX3397, a CSF1R inhibitor that can deplete microglia, while sleep amount at 25°C was unaffected. These observations suggest that microglia play a pivotal role in modulating the homeostatic regulation of sleep in response to the fluctuations in ambient temperature.
    Keywords:  Microglia; Sleep; Temperature
    DOI:  https://doi.org/10.1186/s12576-024-00929-0
  7. Nat Commun. 2025 Jan 22. 16(1): 956
      Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies. The microglial-dependent regulation of cerebral blood flow requires the adenosine triphosphate-sensing P2RY12 receptor and ectonucleotidase CD39 that initiates the dephosphorylation of extracellular adenosine triphosphate into adenosine in both male and female mice. Pharmacological inhibition or CX3CR1-CreER-mediated deletion of CD39 mimics the cerebral blood flow anomalies in microglia-deficient mice and reduces the upsurges of extracellular adenosine following whisker stimulation. Together, these results suggest that the microglial CD39-initiated breakdown of extracellular adenosine triphosphate co-transmitter is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.
    DOI:  https://doi.org/10.1038/s41467-025-56093-5
  8. Cell Death Discov. 2025 Jan 19. 11(1): 16
      The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted from additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to the stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes-CAPG, LGALS3BP, NRIP1, and P2RY12-were found to share regulatory patterns in response to both aging and extrinsic activation. An in-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human-aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.
    DOI:  https://doi.org/10.1038/s41420-025-02295-1
  9. J Neurosci. 2025 Jan 21. pii: e1337242025. [Epub ahead of print]
      Microglia respond to cytotoxic protein aggregates associated with the progression of neurodegenerative disease. Pathological protein aggregates activate the microglial NLRP3 inflammasome resulting in proinflammatory signaling, secretion, and potentially pyroptotic cell death. We characterized mixed sex primary mouse microglia exposed to microbial stressors and alpha synuclein preformed fibrils (αsyn PFFs) to identify cellular mechanisms related to Parkinson's disease. Microglia package and release the endosome fate regulator Coronin1A (Coro1A) in EVs in an Nlrp3-dependent manner in widely used experimental activation conditions. We were surprised to find that Coro1A packaging and release was not Nlrp3-dependent in αsyn PFF exposure conditions. Coro1A-/- microglia exposed to αsyn PFFs trafficked more αsyn to lysosomal compartment increasing lysosomal membrane permeabilization. This corresponds to a decrease in αsyn released in EVs suggesting that Coro1A functions to shunt pathological proteins to a secretory pathway to attenuate lysosomal stress. αsyn PFF driven lysosomal stress resulting from Coro1a loss was associated with enhanced cytotoxicity. Intrinsic apoptosis signaling was unaffected, but we observed elevated cytosolic cathepsin B and the presence of a cathepsin associated 55kD PARP cleavage product. Post-mortem analysis of the PD mesencephalon supported a role for Coro1a in microglia, revealing elevated levels of Coro1A protein in human PD brains compared to those of healthy donors. Findings are relevant to the distribution of pathological αsyn and indicate that Coro1a protects microglia from lysosomal overload, inflammasome activation, and pyroptotic demise.Significance Statement Microglia are responsible for clearing toxic protein aggregates such as alpha synuclein (αsyn) in Parkinson's Disease (PD). PD is slowly progressive, implying that microglia are under proteinaceous stress for an extended time, maintaining some level of homeostasis while attempting to clear pathologically aggregated proteins. Pathological proteins can overload the lysosomes resulting in rupture, decreasing the ability of microglia to clear protein aggregates, and contributing to a hyperreactive inflammatory state. We determined that the protein Coronin1A functions in microglia to attenuate αsyn-induced lysosomal stress, preventing Nlrp3-inflammasome activation, and cell death. These findings identify a protective cellular mechanism operating in microglia that may contribute to the distribution of pathological proteins into the microenvironment.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1337-24.2025
  10. Mol Neurodegener. 2025 Jan 22. 20(1): 9
       BACKGROUND: Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.
    METHODS: We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau.
    RESULTS: In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice.
    CONCLUSIONS: These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.
    Keywords:  5xFAD; APOE Christchurch; Amyloid; DAM; Microglia; PS19; Resilience; Tau
    DOI:  https://doi.org/10.1186/s13024-024-00793-x
  11. J Pathol. 2025 Jan 20.
      Chitinase 1 (CHIT1), as a chitin-specific hydrolase, significantly influences the progression of Alzheimer's disease (AD) through microglia-associated inflammation and amyloid beta (Aβ) plaque accumulation. However, the precise mechanism of CHIT1 action in AD remains uncertain. The effects of CHIT1 on cerebral blood flow (CBF), hippocampal volume, and cognitive function were investigated in APP/PS1 mice. Protein alterations resulting from CHIT1 overexpression were analyzed using four-dimensional (4D) label-free quantitative (LFQ) protein spectrometry. Additionally, the influence of CHIT1 on microglial electrophysiology was assessed using patch clamp measurements, and its effects on neuroinflammation, phagocytosis, microglia migration, and neuronal apoptosis under AD-like conditions were examined using the cell lines N9, BV-2, and HT-22. CHIT1 ameliorated hippocampal atrophy, hypoperfusion, and cognitive function deficits in the APP/PS1 mouse. CHIT1 regulates microglial function and neuronal protection through its interactions in AD. Increased levels of CHIT1/IDH1 contributed to an anti-inflammatory phenotype in microglia via the Ca2+-activated K+ channel, enhanced microglial phagocytosis, and promoted Aβ clearance. Conversely, knocking down IDH1 reduced the secretion of anti-inflammatory agents and increased the production of inflammatory factors, as well as diminishing the expression of phagocytic factors and inhibiting Aβ endocytosis. Moreover, CHIT1 reduced neuronal apoptosis by diminishing the expression of apoptotic factors. However, IDH1 knockdown abrogated the protective effect of CHIT1 on neurons. CHIT1 exerts a protective role in AD pathogenesis through its interaction with IDH1. The CHIT1/IDH1 pathway promotes Aβ clearance via a shift in microglia toward an anti-inflammatory state and prevents neuronal apoptosis and dysfunction caused by Aβ toxicity. © 2025 The Pathological Society of Great Britain and Ireland.
    Keywords:  Alzheimer's disease; CHIT1; IDH1; microglia; neuroinflammation
    DOI:  https://doi.org/10.1002/path.6387
  12. J Neuroinflammation. 2025 Jan 20. 22(1): 11
       BACKGROUND: Deoxyribonuclease 2 (DNase II) is pivotal in the clearance of cytoplasmic double stranded DNA (dsDNA). Its deficiency incurs DNA accumulation in cytoplasm, which is a hallmark of multiple neurodegenerative diseases. Our previous study showed that neuronal DNase II deficiency drove tau hyperphosphorylation and neurodegeneration (Li et al., Transl Neurodegener 13:39, 2024). Although it has been verified that DNase II participates in type I interferons (IFN-I) mediated autoinflammation and senescence in peripheral systems, the role of microglial DNase II in neuroinflammation and neurodegenerative diseases such as Alzheimer's disease (AD) is still unknown.
    METHODS: The levels of microglial DNase II in triple transgenic AD mice (3xTg-AD) were measured by immunohistochemistry. The cognitive performance of microglial DNase II deficient WT and AD mice was determined using the Morris water maze test, Y-maze test, novel object recognition test and open filed test. To investigate the impact of microglial DNase II deficiency on microglial morphology, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and IFN-I pathway, neuroinflammation, synapses loss, amyloid pathology and tauopathy, the levels of cGAS-STING and IFN-I pathway related protein, gliosis and proinflammatory cytokines, synaptic protein, complement protein, Aβ levels, phosphorylated tau in the brains of the microglial DNase II deficient WT and AD mice were evaluated by immunolabeling, immunoblotting, q-PCR or ELISA.
    RESULTS: We found that the levels of DNase II were significantly decreased in the microglia of 3xTg-AD mice. Microglial DNase II deficiency altered microglial morphology and transcriptional signatures, activated the cGAS-STING and IFN-I pathway, initiated neuroinflammation, led to synapse loss via complement-dependent pathway, increased Aβ levels and tauopathy, and induced cognitive decline.
    CONCLUSIONS: Our study shows the effect of microglial DNase II deficiency and cytoplasmic accumulated dsDNA on neuroinflammation, and reveals the initiatory mechanism of AD pathology, suggesting that DNase II is a potential target for neurodegenerative diseases.
    Keywords:  Alzheimer's disease (AD); DNase II; Double stranded DNA (dsDNA); Neuroinflammation; Type I interferons pathway; cGAS-STING pathway
    DOI:  https://doi.org/10.1186/s12974-025-03333-6
  13. J Neuroimmunol. 2025 Jan 16. pii: S0165-5728(25)00005-0. [Epub ahead of print]399 578525
      Although two-dimensional (2D) histology and immunohistochemistry techniques have long been established and successfully applied to obtain structural information from tissues, recent advances in tissue clearing and expansion approaches combined with light sheet microscopy have led to the realization of three-dimensional (3D) nondestructive pathology, which may revolutionize our knowledge of the morphology of an organ or the whole body in its true state. Employing these 3D technologies, we obtained imaging data of microglia in whole hippocampus of mice. We established a simple procedure to analyze the 3D structures of microglia using the commercial software Amira. Major 3D structural parameters, including the volume of the whole cell, volume of the cell body, Feret's maximum/minimum diameter, number of total branches, fractal dimension, convex hull, and number of intersections,were measured. We found that lipopolysaccharide administration markedly changed multiple 3D morphological parameters of microglia. 3D analysis of microglial structures provides a more comprehensive evaluation than 2D analysis, which can be applied in future neuroscience research.
    Keywords:  3D visualization; Amira; Immune inflammation; Microglia; Tissue clearing and expansion
    DOI:  https://doi.org/10.1016/j.jneuroim.2025.578525
  14. J Biophotonics. 2025 Jan 22. e202400468
      Neuroinflammation plays a key role in the development of neurodegenerative diseases, with microglia regulating this process through pro-inflammatory M1 and anti-inflammatory M2 phenotypes. Studies have shown that human umbilical cord mesenchymal stem cells (hUCMSCs) modulate neuroinflammation by secreting anti-inflammatory cytokines. Photobiomodulation (PBM), a non-invasive therapy, has demonstrated significant potential in alleviating neuroinflammation. This study examines the combined effects of PBM and hUCMSCs in an in vitro microglial inflammation model and an LPS-induced mouse model. The results show that PBM-pretreated hUCMSCs promoted M2 polarization and improved cognitive function in mice by downregulating the Notch signaling pathway, suggesting a promising new approach for treating neurodegenerative diseases.
    Keywords:  human mbilical cord mesenchymal stem cells; microglial polarization; neuroinflammation; photobiomodulation
    DOI:  https://doi.org/10.1002/jbio.202400468
  15. Curr Issues Mol Biol. 2025 Jan 04. pii: 28. [Epub ahead of print]47(1):
      The streptozotocin-induced rat model of diabetic retinopathy presents similarities to the disease observed in humans. After four weeks following the induction of diabetes, the rats experience vision impairment. During this crucial four-week period, significant changes occur, with vascular damage standing out as a clinically significant factor, alongside neovascularization. While redox imbalance, activation of microglia, secretion of pro-inflammatory cytokines, and neuronal cell death are also observed, the latter remains an emerging hypothesis requiring further exploration. This review is a comprehensive and up-to-date chronological depiction of the progression of diabetic retinopathy within the initial four weeks of hyperglycemia, which precede the onset of vision loss. The data are structured in weekly changes. In the first week, oxidative stress triggers the activation of retinal microglia, which produces inflammation, leading to altered neurotransmission. The second week is characterized by leukostasis, which promotes ischemia, while neural degeneration begins and is accompanied by a simultaneous increase in vessel permeability. The progression of redox and inflammatory imbalances characterized the third week. Finally, in the fourth week, significant developments occur as vessels dilate and become tortuous, neovascularization develops, and retinal thickness diminishes, ultimately leading to vision loss. Through this clearly structured outline, this review aims to delineate a framework for the progression of streptozotocin-induced diabetic retinopathy.
    Keywords:  diabetic retinopathy; inflammation; microglia; oxidative stress; rat
    DOI:  https://doi.org/10.3390/cimb47010028
  16. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00077-4. [Epub ahead of print]143 387-409
      Lipids play an essential role in synaptic function, significantly impacting synaptic physiology through their dynamic nature and signaling capabilities. Membrane lipids, including cholesterol, phospholipids, and gangliosides, are crucial for synaptic organization and function. They act as structural integrators and signaling molecules, guiding vesicle intracellular movement and regulating enzyme activity to support neuronal activity. The lipid compositions of pre-synaptic and post-synaptic membranes influence vesicle generation and receptor mobility, highlighting their active involvement in synaptic processes. Astrocytes also contribute to synaptic health by upholding the blood-brain barrier, regulating ion levels, and providing metabolic support. Lipid-mediated processes control synaptic plasticity and development, with astrocytes playing a crucial role in glutamate homeostasis. Amyloid-beta and Tau proteins are key in Alzheimer's disease (AD), where synaptic disruption leads to cognitive deficits. Clathrin-mediated endocytosis (CME) and caveolin-mediated endocytosis are critical pathways for lipid-mediated synaptic function, with disruptions in these pathways contributing to AD pathogenesis.
    Keywords:  Alzheimer’s disease; Amyloid beta; Endocytosis; Lipid metabolism; Microglial activation; Synaptic dysfunction; Tau protein
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.08.002
  17. Adv Mater. 2025 Jan 21. e2417869
      Depression is a common psychiatric disorder, and monoamine-based antidepressants as first-line therapy remain ineffective in some patients. The synergistic modulation of neuroinflammation and neuroplasticity could be a major strategy for treating depression. In this study, an inflammation-targeted microglial biomimetic system, PDA-Mem@M, is reported for treating depression. Microglial membrane-coated nanoparticles penetrate the blood-brain barrier and facilitate microglial targeting. Subsequently, owing to the excellent free radical-scavenging capacity, PDA-Mem@M attenuate the brain inflammatory microenvironment. After on-demand release from the nanoparticles, memantine increases the expression of brain-derived neurotrophic factors and reverses the loss of synaptic dendritic spines. Further, in vivo studies demonstrate that PDA-Mem@M effectively alleviate depression-like behaviors to a greater extent than memantine or polydopamine nanoparticles (PDA) monotherapy. This synergistic strategy, with satisfactory biosafety and strong anti-inflammatory and synaptic plasticity restoration effects, is conducive to advances in depression therapy.
    Keywords:  depression; memantine; microglia membrane; polydopamine
    DOI:  https://doi.org/10.1002/adma.202417869
  18. Nat Commun. 2025 Jan 22. 16(1): 918
      Caspases are known to mediate neuronal apoptosis during brain development. However, here we show that nonapoptotic activation of caspase-3 at presynapses drives microglial synaptic phagocytosis. Real-time observation and spatiotemporal manipulation of synaptic caspase-3 in the newly established, mouse-derived culture system demonstrate that increased neuronal activity triggers localized presynaptic caspase-3 activation, facilitating synaptic tagging by complements. High-resolution live imaging reveals that caspase-3 activation promotes synapse-selective complement-dependent microglial phagocytosis without axonal shearing. Furthermore, activity-dependent caspase-3 activation at inhibitory presynapses induces microglial phagocytosis in mice and increases seizure susceptibility. This increased susceptibility is reversed by genetic depletion of microglial complement receptors. Thus, localized, nonapoptotic caspase activity guides complement-dependent microglial synaptic phagocytosis and remodels neuronal circuits.
    DOI:  https://doi.org/10.1038/s41467-025-56342-7
  19. Mol Neurodegener. 2025 Jan 20. 20(1): 8
       BACKGROUND: Age is the principal risk factor for neurodegeneration in both the retina and brain. The retina and brain share many biological properties; thus, insights into retinal aging and degeneration may shed light onto similar processes in the brain. Genetic makeup strongly influences susceptibility to age-related retinal disease. However, studies investigating retinal aging have not sufficiently accounted for genetic diversity. Therefore, examining molecular aging in the retina across different genetic backgrounds will enhance our understanding of human-relevant aging and degeneration in both the retina and brain-potentially improving therapeutic approaches to these debilitating conditions.
    METHODS: Transcriptomics and proteomics were employed to elucidate retinal aging signatures in nine genetically diverse mouse strains (C57BL/6J, 129S1/SvlmJ, NZO/HlLtJ, WSB/EiJ, CAST/EiJ, PWK/PhK, NOD/ShiLtJ, A/J, and BALB/cJ) across lifespan. These data predicted human disease-relevant changes in WSB and NZO strains. Accordingly, B6, WSB, and NZO mice were subjected to human-relevant in vivo examinations at 4, 8, 12, and/or 18M, including: slit lamp, fundus imaging, optical coherence tomography, fluorescein angiography, and pattern/full-field electroretinography. Retinal morphology, vascular structure, and cell counts were assessed ex vivo.
    RESULTS: We identified common molecular aging signatures across the nine mouse strains, which included genes associated with photoreceptor function and immune activation. Genetic background strongly modulated these aging signatures. Analysis of cell type-specific marker genes predicted age-related loss of photoreceptors and retinal ganglion cells (RGCs) in WSB and NZO, respectively. Fundus exams revealed retinitis pigmentosa-relevant pigmentary abnormalities in WSB retinas and diabetic retinopathy (DR)-relevant cotton wool spots and exudates in NZO retinas. Profound photoreceptor dysfunction and loss were confirmed in WSB. Molecular analyses indicated changes in photoreceptor-specific proteins prior to loss, suggesting photoreceptor-intrinsic dysfunction in WSB. In addition, age-associated RGC dysfunction, loss, and concomitant microvascular dysfunction were observed in NZO mice. Proteomic analyses revealed an early reduction in protective antioxidant processes, which may underlie increased susceptibility to DR-relevant pathology in NZO.
    CONCLUSIONS: Genetic context is a strong determinant of retinal aging, and our multi-omics resource can aid in understanding age-related diseases of the eye and brain. Our investigations identified and validated WSB and NZO mice as improved preclinical models relevant to common retinal neurodegenerative diseases.
    Keywords:  Aging; Diabetic retinopathy; Genetic diversity; NZO; Proteomics; RNA-sequencing; Retina; Retinal vascular disease; Retinitis pigmentosa; WSB
    DOI:  https://doi.org/10.1186/s13024-025-00800-9
  20. Rev Neurosci. 2025 Jan 24.
      Fast spiking parvalbumin (PV) interneuron is an inhibitory gamma-aminobutyric acid (GABA)ergic interneuron diffused in different brain networks, including the cortex and hippocampus. As a key component of brain networks, PV interneurons collaborate in fundamental brain functions such as learning and memory by regulating excitation and inhibition (E/I) balance and generating gamma oscillations. The unique characteristics of PV interneurons, like their high metabolic demands and long branching axons, make them too vulnerable to stressors. Neuroinflammation is one of the most significant stressors that have an adverse, long-lasting impact on PV interneurons. Neuroinflammation affects PV interneurons through specialized inflammatory pathways triggered by cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6). The crucial cells in neuroinflammation, microglia, also play a significant role. The destructive effect of inflammation on PV interneurons can have comprehensive effects and cause neurological disorders such as schizophrenia, Alzheimer's disease (AD), autism spectrum disorder (ASD), and bipolar disorder. In this article, we provide a comprehensive review of mechanisms in which neuroinflammation leads to PV interneuron hypofunction in these diseases. The integrated knowledge about the role of PV interneurons in cognitive networks of the brain and mechanisms involved in PV interneuron impairment in the pathology of these diseases can help us with better therapeutic interventions.
    Keywords:  Alzheimer’s disease; autism; excitatory inhibitory balance; inflammation; microglia; schizophrenia
    DOI:  https://doi.org/10.1515/revneuro-2024-0153
  21. Brain Commun. 2025 ;7(1): fcae386
      The extent to which glial cell turnover features in successful remyelination is unclear. In this study, the rat caudal cerebellar peduncle-ethidium bromide lesion model was used to profile oligodendroglial and microglial/macrophage cell death and proliferation dynamics over the course of repair. Lesioned and control tissue was co-labelled with antibody markers for cell identity, proliferation, and apoptosis (TUNEL assay), then imaged at full thickness using confocal microscopy and quantified using custom CellProfiler pipelines. Early remyelination time points were marked by an increased density of total proliferating cells, including oligodendrocyte progenitor cells. Late remyelination time points featured increased TUNEL+ oligodendrocyte progenitor cells: however, most TUNEL+ cells within remyelinating lesions were Iba1+ microglia/macrophages. These results indicate that repairing lesions are characterized by a high degree of glial cell death and suggest that monitoring cell death-related by-products might have clinical value in the setting of remyelination.
    Keywords:  cell death; microglia; oligodendrocyte; oligodendrocyte progenitor cell; remyelination
    DOI:  https://doi.org/10.1093/braincomms/fcae386