bims-micgli 2025-12-14 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–12–14
twenty-two papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Shape-shifting microglia respond to neuronal hyperexcitability.
Deletion of neuronal Idol ameliorates Alzheimer's disease-related pathologies via APOE receptors.
Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
Dynamic changes in mitochondria support phenotypic flexibility of microglia.
Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4.
Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer's disease mouse models.
Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease.
Microglia and Myeloid Cell Populations of the Developing Mouse Retina.
Bridging veins in Alzheimer's disease: Decoding waste clearance failure.
Microglia in the crosstalk between peripheral and central nervous systems in Parkinson's disease.
Plasma soluble TREM2 is associated with plasma pTau-181 and pTau-231 in cognitively normal older adults at risk of Alzheimer's disease.
RetSat Knockout Mitigates Hypoxia-Induced Microglial Activation by Enhancing Lipid Droplets Degradation.
Acute neuroinflammation induces prolonged transcriptional reprogramming in microglia.
PP2A methylesterase, PME-1, and PP2A methyltransferase, LCMT-1, control sensitivity to impairments caused by injury-related oligomeric tau.
Chimeric human organoid and mouse brain slice co-cultures to study microglial function.
A single-cell transcriptomic atlas reveals resident dendritic-like cells in the zebrafish brain parenchyma.
Caspase-8 expression in CD8+ T cells promotes pathogen restriction in the brain during Toxoplasma gondii infection.
FGF Receptor Signaling in Oligodendrocytes Regulates Synaptic Plasticity, Learning, and Memory in the Adult Brain.
Interaction Between Microglial Lipid Droplet Metabolism and Immune Polarisation After Stroke: Mechanisms and Therapeutic Prospects.
The Neurochemical Landscape of Oligodendrocyte Physiology: From Myelination to Metabolic and Synaptic Modulation.
Microbial production of short-chain fatty acids attenuates long-term neurologic impairment after traumatic brain injury.
Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer's disease.

Immunity. 2025 Dec 09. pii: S1074-7613(25)00504-7. [Epub ahead of print]58(12): 2927-2930

Shape-shifting microglia respond to neuronal hyperexcitability.

Clara Alice Musi, Diego Gomez-Nicola.

The initial responses of microglia to neuronal stress or altered network activity are poorly characterized. Xie and colleagues show that during TDP-43-related neurodegeneration, microglia detect early neuronal hyperactivity and transition into a distinct rod-shaped state. This study uncovers a microglial state that precedes overt neuronal loss, shedding new light on the earliest stages of neurodegeneration.

DOI: https://doi.org/10.1016/j.immuni.2025.11.002
Alzheimers Dement. 2025 Dec;21(12): e70949

Deletion of neuronal Idol ameliorates Alzheimer's disease-related pathologies via APOE receptors.

Hande Karahan, Kelly Hartigan, Md Mamun Al-Amin, Sutha K John, Brianne McCord, H R Sagara Wijeratne, Dominic J Acri, Daniel C Smith, Luke C Dabin, Hannah M Rondon Cordero, Byungwook Kim, Do-Hun Lee, Jungsu Kim.

   INTRODUCTION: Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aβ) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL), an enzyme that ubiquitinates LDLR for degradation, would increase endogenous LDLR levels and attenuate amyloid pathology.
METHODS: To investigate the cell-type-specific role of IDOL, we generated Idol conditional knockout mice on an Aβ-amyloidosis mouse model and performed biochemical, histological, and multi-omics analyses.
RESULTS: We demonstrated that neuronal, but not microglial, Idol deletion reduced amyloid accumulation and altered brain LDLR and APOE levels, indicating the critical role of neuronal IDOL-LDLR in amyloid pathology. In addition, neuronal Idol deletion increased the levels of Reelin receptors important for synaptic function, and single-nuclei RNA sequencing revealed significant changes associated with synaptic organization.
DISCUSSION: Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer's disease pathogenesis by regulating the levels of brain APOE receptors.
HIGHLIGHTS: Neuronal, but not microglial, Idol deletion reduces amyloid burden and modulates brain APOE and LDLR levels. Deletion of neuronal Idol increases the levels of APOER2 and VLDLR, the Reelin receptors, in the brain. Single-nuclei RNA sequencing highlights the neuronal IDOL's impact on inhibitory neurons and synaptic organization. Targeting neuronal IDOL may provide multiple therapeutic benefits in Alzheimer's disease by modulating APOE receptors.

Keywords:  APOE; APOER2 (LRP8); Amyloid beta; IDOL (MYLIP); LDLR; VLDLR

DOI:  https://doi.org/10.1002/alz.70949
Nat Commun. 2025 Dec 12. 16(1): 11104

Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.

Alicia N Pietramale, Xhoela Bame, Megan E Doty, Kiera E Schwarz, Robert A Hill.

Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging and ultrastructural analyses of microglia mitochondria in mice and human tissue, revealing that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. Microtubules and hexokinase 2 mirror this uneven mitochondrial distribution indicating that these cytoskeletal and metabolic components are linked to mitochondrial organization in microglia. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning. Moreover, microglial processes that surveil and acutely respond to damage do not contain mitochondria.

DOI: https://doi.org/10.1038/s41467-025-66708-6
Nat Commun. 2025 Dec 12. 16(1): 11103

Dynamic changes in mitochondria support phenotypic flexibility of microglia.

Katherine Espinoza, Ari W Schaler, Daniel T Gray, Arielle R Sass, Adrian Escobar, Kamilia Moore, Megan E Yu, Casandra G Chamorro, Lindsay M De Biase.

Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglial phenotypes and phenotypic remodeling that takes place over hours to months.

DOI: https://doi.org/10.1038/s41467-025-66709-5
J Neuroinflammation. 2025 Dec 11.

Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4.

Georgia L Nolt, Lesley R Golden, Shealee P Thorpe, Jessica L Funnell, Isaiah O Stephens, Gabriela Hernandez, Steven M MacLean, Chloe C Lucido, Chesney R Brock, Akhil V Pallerla, Darcy R Adreon, Holden C Williams, Josh M Morganti, Lance A Johnson.

  Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms.

Keywords:  Apolipoprotein E; Brain; Gliosis; Lipid metabolism; Microglia; Myelination

DOI:  https://doi.org/10.1186/s12974-025-03639-5
Nat Commun. 2025 Dec 09. 16(1): 10969

Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer's disease mouse models.

Timothy J Trinklein, Stanislav S Rubakhin, Samuel Okyem, Seth W Croslow, Marisa Asadian, K R Sabitha, Orly Lazarov, Fan Lam, Jonathan V Sweedler.

The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer's disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APPNL-G-F mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging, trapped ion mobility spectrometry, and fluorescence microscopy. Our approach improves detectability and spatial-chemical resolution. We couple these measurements with a computational pipeline for multimodal image coregistration and discovery of plaque-altered lipids. Here, we show the lipids in and around Aβ plaques are highly heterogeneous. Integration of our data with existing spatial transcriptomics data suggests that region-specific accumulation of simple gangliosides is likely driven by lysosomal degradation of complex species. Together, this work provides a generalizable framework to understand lipid alterations within the Aβ plaque microenvironment.

DOI: https://doi.org/10.1038/s41467-025-65956-w
Transl Neurodegener. 2025 Dec 12. 14(1): 67

Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease.

Godfried Dougnon, Hideaki Matsui.

  Lipofuscin, a marker of aging, is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons. Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradation. However, recent findings suggest that lipofuscin may play a role in modulating age-related neurodegenerative processes, and several questions remain unanswered. For instance, why do lipofuscin granules accumulate preferentially in aged neurons and microglia? What happens to these pigments upon neuronal demise? Particularly in neurodegenerative diseases like Alzheimer's disease (AD), why does amyloid β (Aβ) deposition usually begin in late adulthood or during aging? Why do lipofuscin and amyloid plaques appear preferentially in grey matter and rarely in white matter? In this review, we argue that lipofuscin should be revisited not as a simple biomarker of aging, but as a potential modulator of neurodegenerative diseases. We synthesize emerging evidence linking lipofuscin to lysosomal dysfunction, oxidative stress, lipid peroxidation and disease onset-mechanisms critically implicated in neurodegeneration. We also explore the potential interactions of lipofuscin with Aβ and their spatial location, and summarize evidence showing that lipofuscin may influence disease progression via feedback loops affecting cellular clearance and inflammation. Finally, we propose future research directions toward better understanding of the mechanisms of lipofuscin accumulation and improved lysosomal waste clearance in aging.

Keywords:  Aging; Alzheimer’s disease; Amyloid beta (Aβ); Autofluorescence; Inflammation; Lipofuscin; Lysosomal dysfunction; Neurodegeneration; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1186/s40035-025-00529-x
Glia. 2026 Feb;74(2): e70115

Microglia and Myeloid Cell Populations of the Developing Mouse Retina.

Sage Martineau, Juan C Valdez-Lopez, Samantha Zarnick, Jeremy N Kay.

  Microglia make important contributions to central nervous system (CNS) development, but the breadth of their distinct developmental functions remains poorly understood. The mouse retina has been a key model system for understanding fundamental mechanisms controlling the assembly of the CNS. To gain insight into where and how microglia might influence retinal development, here we identified molecularly unique myeloid cell populations that are selectively present during development and characterized their anatomical locations. Development-specific transcriptional states were identified using single-cell (sc) and single-nucleus RNA-sequencing (RNA-seq) across multiple timepoints. Transcriptional states were validated in vivo by histological staining for key RNA and/or protein markers. Several of these development-specific myeloid populations have been described before in brain scRNA-seq atlases but not validated in vivo, while others are unique to our retinal dataset. We identify two closely related microglial populations, labeled by the Spp1 and Hmox1 genes, that are distinguished mainly by transcriptional targets of the NRF2 transcription factor. Both types are present selectively within the developing retinal nerve fiber layer where they engulf neurons and astrocytes undergoing developmental cell death. Hmox1+ microglia were also localized selectively at the wavefront of developing vasculature during retinal angiogenesis, suggesting that developmental events associated with angiogenesis modulate NRF2 activity and thereby induce microglia to switch between the Spp1+ and Hmox1+ states. Overall, our results identify transcriptional profiles that define specific populations of retinal microglia, opening the way to future investigations of how these programs support microglial functions during development.

Keywords:  efferocytosis; macrophage; osteopontin; phagocytosis; single‐cell sequencing; vascular development

DOI:  https://doi.org/10.1002/glia.70115
J Exp Med. 2026 Feb 02. pii: e20252240. [Epub ahead of print]223(2):

Bridging veins in Alzheimer's disease: Decoding waste clearance failure.

Ting Du, Guojun Liu, Maiken Nedergaard.

Perivenous tunnels surrounding bridging veins terminate at "arachnoid cuff exit" (ACE) points, which enable waste efflux from the brain. Smyth et al. (https://doi.org/10.1084/jem.20251860) show that amyloid deposits in ACE in Alzheimer's disease mice and human samples identify a potential new therapeutic target.

DOI: https://doi.org/10.1084/jem.20252240
Transl Neurodegener. 2025 Dec 11. 14(1): 66

Microglia in the crosstalk between peripheral and central nervous systems in Parkinson's disease.

Tianbai Li, Tao Qiu, Fei Jiang, Huaibin Cai, Weidong Le.

  Parkinson's disease (PD) is increasingly recognized as a multisystem disorder involving pathological α-synuclein (α-syn) accumulation and widespread neuroimmune dysregulation. Microglia, the resident immune cells in the central nervous system (CNS), are pivotal mediators of the bidirectional communication between the CNS and peripheral systems. In addition to sensing neuronal injury and α-syn pathology, microglia dynamically respond to peripheral immune signals, including circulating cytokines, immune cell infiltration, and microbial metabolites, through pattern recognition receptors such as Toll-like and NOD-like receptors. Furthermore, microglia regulate blood-brain barrier integrity, modulate peripheral immune cell recruitment, interact with meningeal lymphatic vessels, and contribute to the propagation of α-syn within the CNS and along the gut-brain axis. However, a comprehensive framework encompassing their diverse roles in peripheral-central immune crosstalk remains underdeveloped. This review synthesizes recent advances elucidating how microglia link the CNS to peripheral immune and metabolic signals in PD. We further highlight microglial contributions to α-syn propagation along the gut-brain axis and discuss how their functional states influence disease progression. A deeper understanding of microglial involvement in this complex neuroimmune interface may inform the development of effective and system-level therapeutic strategies for PD.

Keywords:  Gut microbial metabolites; Inflammation; Microglia; Parkinson’s disease; α-Synuclein

DOI:  https://doi.org/10.1186/s40035-025-00531-3
J Alzheimers Dis. 2025 Dec 09. 13872877251400780

Plasma soluble TREM2 is associated with plasma pTau-181 and pTau-231 in cognitively normal older adults at risk of Alzheimer's disease.

Prita R Asih, Cameron W Morris, Hong Wang, Steve Pedrini, Kathryn Goozee, Simon M Laws, Pratishtha Chatterjee, Kevin Taddei, Hamid R Sohrabi, Stephanie R Rainey-Smith, Chai K Lim, Gilles J Guillemin, Thomas K Karikari, Colin L Masters, Henrik Zetterberg, Kaj Blennow, Nicholas J Ashton, Ralph N Martins.

  BackgroundCSF and blood soluble TREM2 (sTREM2) levels have been found to increase at early stage of Alzheimer's disease (AD). The relationships between sTREM2, AD-related biomarkers, and other neuroinflammation biomarkers remain unclear. Moreover, the impact of rare variants in TREM2 gene (R47H/R62H), which are associated with increased risk of AD, on plasma sTREM2 has not been elucidated.ObjectiveInvestigate the association of plasma sTREM2 levels with brain amyloid-β (Aβ) load and AD-related blood biomarkers, i.e., phosphorylated tau (pTau)-181, pTau-231, GFAP, NFL, and other neuroinflammation and peripheral inflammation markers in cognitively normal (CN) older adults at risk of AD (CN Aβ+) compared to CN Aβ-, including the effect of AD-linked TREM2 rare variants.MethodsPlasma sTREM2 concentrations were measured by MesoScale Discovery (MSD) assay from the KARVIAH cohort. Participants underwent cognitive tests and PET amyloid imaging. Genetic data and blood biomarkers were included for correlation analysis. Associations with plasma sTREM2 were investigated upon stratification by PET-Aβ load SUVR ((CN Aβ- (n = 65) and CN Aβ+ (n = 35)) as the main analysis. A subgroup analysis based on the TREM2 R47H and R62H genotype was conducted as exploratory analysis.ResultsPlasma sTREM2 positively correlated with plasma pTau181, and pTau231 in CN Aβ+ group. Plasma sTREM2 positively correlated with serum microglial kynurenine pathway metabolites. Plasma sTREM2 and brain Aβ load were higher in R47H TREM2 carriers compared to non-carriers.ConclusionsOur findings suggest plasma sTREM2 relates to downstream tau processes in amyloid-positive individuals, providing novel insights into the roles of peripheral TREM2 signaling that reflects microglial activity in early AD neuropathological development.

Keywords:  Alzheimer's disease; R47H TREM2; biomarkers; microglia activation; neuroinflammation; plasma p-tau; plasma sTREM2

DOI:  https://doi.org/10.1177/13872877251400780
Glia. 2026 Feb;74(2): e70118

RetSat Knockout Mitigates Hypoxia-Induced Microglial Activation by Enhancing Lipid Droplets Degradation.

Wenyu Hu, Shuoshuo Li, Wenjun Shi, Ping Zhang, Xue Zhang, Ying Liu, Xin Zhou, Peng Shi, Junliang Yuan, Zengqiang Yuan, Jinbo Cheng.

  Exposure to hypoxic environments leads to neurological dysfunction, with recent studies implicating microglia-derived neuroinflammation involved in hypoxia-induced neuronal impairment. However, the underlying pathological mechanisms remain largely unclear. Lipid-droplet-accumulating microglia (LDAM) have been linked to age-related and genetic forms of neurodegeneration, prompting the investigation of their role in hypoxia-induced neuronal impairment. In this study, we observed that hypoxia induced lipid droplets accumulation in microglia, accompanied by increased levels of RETSAT, an enzyme involved in lipid metabolism regulation. Conditional knockout of RETSAT in microglia decreased lipid droplets accumulation and alleviates hypoxia-induced microglial-derived neuroinflammation and oxidative stress, both in vitro and in vivo. Our biological studies indicate that the beneficial effects of RETSAT knockout on lipid droplets degradation are primarily mediated through enhanced activity of hormone-sensitive lipase (HSL). Furthermore, we found that the hypoxic adaptation-related RETSAT mutation Q247R promotes microglia lipolysis under hypoxic conditions. These findings suggest that RetSat is a potential therapeutic target for the prevention and treatment of hypoxia-induced microglial activation.

Keywords:  HSL; RetSat; hypoxia; lipid droplets; microglia activation

DOI:  https://doi.org/10.1002/glia.70118
J Neuroinflammation. 2025 Dec 10.

Acute neuroinflammation induces prolonged transcriptional reprogramming in microglia.

Sehoon Moon, Cheol Gyun Kim, Young-Kwang Kim, Cheol-Heui Yun, Min-Kyoo Shin, Hyungseok Seo.

  Acute neuroinflammation rapidly activates brain immune responses, but its lasting effects on microglia are unclear. Using systemic LPS administration and LCMV-Armstrong infection, we found that blood-brain barrier disruption and cytokine shifts resolved within 30 days, yet microglial recovery was incomplete-marked by persistent numerical loss and an IFN-γ-low phenotype in the LPS model and reduced relative abundance in the LCMV model. Single-cell RNA sequencing revealed sustained transcriptional alterations, including disease-associated microglia (DAM) features and a distinct recovery-biased population. These acute signatures overlapped with profiles from Alzheimer's model mice and were enriched in human microglia from multiple sclerosis, Alzheimer's disease, and other neuroinflammatory conditions. Although our observation period was shorter than the chronic course of these diseases, the persistence of disease-like microglial states suggests that transient inflammation can prime the brain for long-term vulnerability. Targeting this primed state may offer new strategies to prevent or mitigate neurodegenerative pathology.

Keywords:  Acute neuroinflammation; Microglia; Transcriptomic reprogramming

DOI:  https://doi.org/10.1186/s12974-025-03572-7
Alzheimers Dement. 2025 Dec;21(12): e70947

PP2A methylesterase, PME-1, and PP2A methyltransferase, LCMT-1, control sensitivity to impairments caused by injury-related oligomeric tau.

Sowmya N Sundaresh, Edward W Vogel, Christopher D Hue, Hong Zhang, Anna Staniszewski, Hanna L Berman, Zafar Gill, Kesava Asam, Siqi Liang, Liwei Shen, Madhumathi Gnanaprakash, Erica Acquarone, Antonio Masone, Mauro Fà, Nicholas M Kanaan, Barclay Morrison, Ottavio Arancio, Russell E Nicholls.

   INTRODUCTION: Oligomeric species of tau are a hallmark of Alzheimer's disease (AD). Given the evidence implicating protein phosphatase 2A (PP2A) in the molecular pathogenesis of tauopathies, we sought to determine whether manipulating the expression of enzymes that regulate PP2A activity, such as leucine carboxyl methyltransferase 1 (LCMT-1) and protein methylesterase 1 (PME-1), would alter pathological responses to oligomeric tau.
METHODS: We tested the effect of LCMT-1 and PME-1 overexpression on cognitive and electrophysiological impairments caused by exposure to either recombinant oligomeric human tau or oligomeric tau prepared from mice subjected to blast-induced traumatic brain injury.
RESULTS: We found that LCMT-1 overexpression reduced sensitivity while PME-1 overexpression increased sensitivity to tau-induced impairments. Moreover, shockwave exposure increased the propensity of endogenous tau to form toxic oligomers.
DISCUSSION: These results suggest that manipulating LCMT-1 or PME-1 activity may represent novel therapeutic approaches for disorders involving exposure to pathogenic forms of oligomeric tau.
HIGHLIGHTS: LCMT-1 and PME-1 overexpression alters sensitivity to oligomeric tau-induced impairments. Blast-induced traumatic brain injury increases the propensity of tau to oligomerize. Pathogenic tau-induced cognitive impairments were dependent on its oligomeric form.

Keywords:  Alzheimer's disease; cognitive dysfunction; neurodegeneration; protein phosphatase 2A; tau; traumatic brain injury

DOI:  https://doi.org/10.1002/alz.70947
Cell Rep. 2025 Dec 10. pii: S2211-1247(25)01428-7. [Epub ahead of print]44(12): 116656

Chimeric human organoid and mouse brain slice co-cultures to study microglial function.

Vasiliki Panagiotakopoulou, Marc Welzer, Olmo Ruiz Ormaechea, Diana Werner, Lena Erlebach, Anika Bühler, Ulrike Obermüller, Jonas J Neher, Mathias Jucker, Deborah Kronenberg-Versteeg.

  Studying the dynamic role of microglia in brain development and neurodegenerative diseases requires models that closely resemble the human brain environment. While human induced pluripotent stem cell (iPSC)-derived organoids (hORGs) effectively reproduce key neuronal and certain glial cell types, modeling human microglia in vitro remains challenging. Inspired by recent approaches demonstrating enhanced microglial maturation in hORGs transplanted into mouse brains, we develop a chimeric model by co-culturing hORGs with mouse brain slice cultures (mBSCs). This system reveals cross-species interactions associated with an earlier onset of cortical neuronal differentiation markers in the hORGs. Human iPSC-derived microglia, pre-differentiated in mBSCs, migrate into the hORGs and adopt ramified morphology. They remain viable for several months and respond to laser-induced injury, demonstrating long-term functionality. This in vitro model supports long-term study of human microglia in a brain-like environment, providing a platform for mechanistic studies and screening compounds that target microglial function.

Keywords:  CP: neuroscience; CP: stem cell research; cerebral organoids; chimeric in vitro model; human microglia; xenotransplantation

DOI:  https://doi.org/10.1016/j.celrep.2025.116656
Elife. 2025 Dec 11. pii: RP91427. [Epub ahead of print]13

A single-cell transcriptomic atlas reveals resident dendritic-like cells in the zebrafish brain parenchyma.

Mireia Rovira, Giuliano Ferrero, Magali Miserocchi, Alice Montanari, Ruben Lattuca, Valerie Wittamer.

  Recent studies have highlighted the heterogeneity of the immune cell compartment within the steady-state murine and human CNS. However, it is not known whether this diversity is conserved among non-mammalian vertebrates, especially in the zebrafish, a model system with increasing translational value. Here, we reveal the complexity of the immune landscape of the adult zebrafish brain. Using single-cell transcriptomics, we characterized these different immune cell subpopulations, including cell types that have not been or have only been partially characterized in zebrafish so far. By histology, we found that, despite microglia being the main immune cell type in the parenchyma, the zebrafish brain is also populated by a distinct myeloid population that shares a gene signature with mammalian dendritic cells (DC). Notably, zebrafish DC-like cells rely on batf3, a gene essential for the development of conventional DC1 in the mouse. Using specific fluorescent reporter lines that allowed us to reliably discriminate DC-like cells from microglia, we quantified brain myeloid cell defects in commonly used irf8-/-, csf1ra-/-, and csf1rb-/- mutant fish, revealing previously unappreciated distinct microglia and DC-like phenotypes. Overall, our results suggest a conserved heterogeneity of brain immune cells across vertebrate evolution and also highlights zebrafish-specific brain immunity characteristics.

Keywords:  dendritic cells; evolutionary biology; immune repertoire; microglia; neuroscience; zebrafish

DOI:  https://doi.org/10.7554/eLife.91427
Sci Adv. 2025 Dec 12. 11(50): eadz4468

Caspase-8 expression in CD8+ T cells promotes pathogen restriction in the brain during Toxoplasma gondii infection.

Lydia A Sibley, Maureen N Cowan, Abigail G Kelly, NaaDedee A Amadi, Isaac W Babcock, Sydney A Labuzan, Michael A Kovacs, Samantha J Batista, John R Lukens, Tajie H Harris.

Cell death is an integral restriction mechanism against intracellular pathogens. We have previously reported extensive cell death in the brain during infection with the intracellular parasite, Toxoplasma gondii. Here, we focus on the role of caspase-8, a regulator of extrinsic apoptosis, during T. gondii infection. We find that Casp8-/-Ripk3-/- mice have increased brain parasite burden in comparison to controls and succumb to infection despite the generation of robust immune responses. We observed that neurons, astrocytes, and CD8+ T cells had high rates of parasite interactions in Casp8-/-Ripk3-/- mice compared to wild-type mice. While Casp8 deficiency in neurons and astrocytes did not affect control of infection, deletion of Casp8 in CD8+ T cells led to impaired survival, increased parasite burden, and direct infection of CD8+ T cells in the brain. We conclude that in addition to well-characterized effector functions, CD8+ T cells use caspase-8 to control T. gondii in the brain.

DOI: https://doi.org/10.1126/sciadv.adz4468
Glia. 2026 Feb;74(2): e70123

FGF Receptor Signaling in Oligodendrocytes Regulates Synaptic Plasticity, Learning, and Memory in the Adult Brain.

M Furusho, B Das, R Yan, R Bansal, A Ishii.

  Oligodendrocytes (OLs) generate myelin sheaths around axons and maintain them to facilitate the propagation of action potentials and support neuronal metabolism and synaptic function. Previously, we have shown that Fibroblast Growth Factor Receptor-1 and -2 (FGFR1/2) signaling is required for oligodendrocyte precursor cell (OPC) expansion, promoting myelin growth during developmental myelination and maintaining myelin/axonal integrity in the spinal cord during adulthood. However, whether OL-lineage cells may affect neuronal synaptic functions and impact memory/learning during adulthood/aging remained largely unknown. Here, we showed that FGFR1/2 signaling in OPCs and OLs is required throughout adulthood and is critical for the long-term maintenance of synaptic activity and memory. Specifically, the lack of FGFR1/2 signaling within OL-lineage cells resulted in the impairment of long-term potentiation (LTP), a reduction in docked synaptic vesicles at the synaptic terminals, deficits in hippocampal-based memory and learning, and β-APP accumulation in older animals. Importantly, we found that there was no loss of OPCs or OLs, myelin degeneration, astrogliosis, microglial activation, or reduction in myelin thickness in the adult hippocampus of mutant mice. Furthermore, the tamoxifen-inducible loss of FGFR1/2 signaling during adulthood also impaired LTP. In addition, the conditional ablation of either FGFR1 or FGFR2 individually in the OL-lineage cells impaired LTP during adulthood, although at different levels. Thus, these observations bring up the possibility that FGFR1/2 signaling in OL-lineage cells may play a potentially novel, previously unrecognized role in OL-neuron communication for the maintenance of synaptic plasticity and memory functions in the normal adult/aging brain.

Keywords:  myelin; myelination; oligodendrocyte

DOI:  https://doi.org/10.1002/glia.70123
Cell Mol Neurobiol. 2025 Dec 07.

Interaction Between Microglial Lipid Droplet Metabolism and Immune Polarisation After Stroke: Mechanisms and Therapeutic Prospects.

Junchi Yang, Dongyan Wang, Xu Dong, Hong Huo, Ruiyu Tao, Youwei Zhang, Zhao Wang, Liping Wang, Ninghui Zhi.

  The interaction between lipid droplet (LD) metabolism and immune polarisation of microglia after stroke plays a key role in the regulation of neuroinflammation and tissue repair. This review analysed the molecular mechanism, spatiotemporal specificity, and the dual role of the LD metabolism-immune axis in microglia after stroke. Microglial LDs can dynamically store neutral lipids and regulate the metabolite-immune network, playing a protective role in the early stage of stroke by isolating pro-inflammatory precursors, inhibiting oxidative stress and iron death, and maintaining energy buffer. Spatiotemporal analysis revealed significant heterogeneity in the distribution and function of LDs across different stages of stroke and in distinct brain areas (infarct core, peri-infarct region, and non-infarct area), directly correlating with the pro-inflammatory/anti-inflammatory phenotypic transformation of microglia. The development of LD-related biomarkers (such as near-infrared imaging), the repurpose of peroxisome proliferator-activated receptor γ agonists (rosiglitazone) and HDAC inhibitors (volinostat), as well as the design of novel drugs (such as Triggering Receptor Expressed on Myeloid Cells 2 agonists and perilipin 2 small interfering RNA) are expected to improve stroke outcomes by transforming metabolic homeostasis and immune balance. Multi-omics technology and intelligent delivery system should be combined to overcome the limitations of the blood-brain barrier, promote the clinical transformation of the "metabolism-immunity" collaborative intervention strategy, and provide a new paradigm for precision treatment of stroke.

Keywords:  Immunopolarisation; Lipid droplet metabolism; Metabolism-immune axis; Microglia; Stroke

DOI:  https://doi.org/10.1007/s10571-025-01646-x
J Neurochem. 2025 Dec;169(12): e70318

The Neurochemical Landscape of Oligodendrocyte Physiology: From Myelination to Metabolic and Synaptic Modulation.

Jorge Correale.

  Oligodendrocytes, traditionally recognized for their role in axonal myelination, are increasingly appreciated as metabolically dynamic and functionally diverse cells integral to central nervous system (CNS) homeostasis. This review delineates the evolving neurochemical landscape of oligodendrocyte physiology, emphasizing their roles beyond myelin production. We explore key processes including lipid metabolism, metabolic coupling with neurons, ion buffering, neurotransmitter signaling, and synaptic modulation. Oligodendrocytes preferentially utilize aerobic glycolysis and support axonal energy metabolism via the export of lactate and phosphocreatine, maintaining ATP levels even in the absence of mitochondria within the myelin sheath. Their capacity for regional and transcriptional heterogeneity allows adaptive responses to local microenvironments and neuronal activity. Lipid biosynthesis and storage mechanisms are intricately regulated through mTORC1, SREBPs, and lipophagy, enabling rapid membrane expansion, and structural integrity during myelination. Furthermore, oligodendrocytes modulate the periaxonal milieu via potassium buffering, pH regulation, and osmotic balance, primarily through Kir channels, carbonic anhydrases, and aquaporins. They also express a wide array of neurotransmitter receptors, enabling bidirectional communication with neurons and activity-dependent modulation of maturation and plasticity. Intracellular signaling pathways such as PI3K/Akt/mTOR, MAPK/ERK, and Wnt/β-catenin orchestrate the integration of metabolic and transcriptional programs. Collectively, these findings redefine oligodendrocytes as active participants in CNS physiology, contributing to neuronal health, circuit plasticity, and responses to injury or disease.

Keywords:  ionic and osmotic buffering; lipid metabolism; metabolic coupling; myelination; oligodendrocytes

DOI:  https://doi.org/10.1111/jnc.70318
J Neuroinflammation. 2025 Dec 09. 22(1): 285

Microbial production of short-chain fatty acids attenuates long-term neurologic impairment after traumatic brain injury.

Zujian Xiong, Brittany P Dodson, Matthew B Rogers, Chaim T Sneiderman, Keri Janesko-Feldman, Vincent Vagni, Mioara Manole, Xuejun Li, Dhivyaa Rajasundaram, Robert S B Clark, Itay Raphael, Michael J Morowitz, Eliana Mariño, Patrick M Kochanek, Ruchira M Jha, Gary Kohanbash, Dennis W Simon.

   BACKGROUND: Traumatic brain injury (TBI) triggers persistent gut microbiome dysbiosis characterized by depletion of short-chain fatty acid (SCFA)-producing bacteria. However, the link between SCFA depletion and long-term neurologic impairment (LTNI) after TBI remains unclear. Previously, we and others noted the involvement of metabolite-sensing receptors and SCFA ligands in mouse models of neurodegenerative diseases, including Alzheimer's. Here, we further investigated SCFA-mediated neuroprotection in LTNI at both microbiome and single-cell resolution using the controlled cortical impact (CCI) model of TBI with a high-yielding SCFA diet to examine their mechanistic role in pathogenesis.
METHODS: C57BL6/J mice were randomized to CCI (6 m/s, 2 mm) or sham surgery. Following surgery, mice were randomized to a study diet based on a balanced modification of the AIN93-G diet containing either 15% high amylose maize starch (HAMS) control diet or acetylated and butyrylated HAMS (HAMSAB) for 6 months to model increased SCFA production by bacterial fermentation in the gut. Morris water maze test and nesting assessment were performed at 1, 3, and 6 months after injury. The longitudinal gut microbiome changes were investigated by 16 S rRNA amplicon and metagenomic sequencing of fecal pellets at baseline, 1 month, and 6 months post-injury. At 6 months, pericontusional tissue was collected for single-cell RNA-sequencing following the 10X Genomics protocol or histologic analysis.
RESULTS: Compared to the HAMS control diet, HAMSAB diet remodeled the CCI murine gut microbiome at an early phase, increased various SCFA-producing taxa, and attenuated neurologic deficits up to 6 months after CCI. In mice fed HAMSAB diet, single-cell transcriptomics and pathway analysis identified the promotion of neurogenesis, including increased doublecortin-positive immature neurons. In myeloid cells, HAMSAB induced an anti-inflammatory phenotype, inhibiting pro-inflammatory signaling interaction such as midkine signaling, and promoted differentiation to disease-associated microglia (DAM). Simultaneously, SCFAs reduced neurodegenerative pathway activity in neurons and glial cells and reduced phosphorylated tau deposition in pericontusional cortex.
CONCLUSIONS: Diet-facilitated microbial production of acetate and butyrate attenuates behavioral deficits of LTNI after TBI and produces enduring benefits at the single-cell level on the neuro-inflammatory and neuro-progenitor responses. This therapeutic approach could have a broader potential to prevent neurodegenerative disease.

Keywords:  Microbiome; Neuro-inflammation; Neurodegeneration; Single-cell sequencing; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12974-025-03615-z
Nat Commun. 2025 Dec 09. 16(1): 10973

Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer's disease.

Desirée Böck, Lisa Tidecks, Maria Wilhelm, Waleed ElGrawani, Sian Duss, Chiara Trevisan, Dalila Vena, Anna Maria Reuss, Lucas Kissling, Matteo Ranucci, Mattia Privitera, Lisa K Polzer, Athena E Economides, Eleonora I Ioannidi, Raquel Mendes, Yanik Weber, Justine Leonardi, Jonas Mumenthaler, Elina Villiger, Romain Goutagny, Chantal Mathis, Lukas Schmidheini, Tanja Rothgangl, Sharan Janjuha, Tommaso Patriarchi, Johannes Bohacek, Yaroslav Sych, Adriano Aguzzi, Jochen Winterer, Konstantinos Kompotis, Gerald Schwank.

Prime editing offers versatile genome modifications with therapeutic potential; yet its use to modulate neural circuitry remains underexplored. Here, we used adeno-associated viral vectors to deliver prime editors into the mouse brain and introduced the naturally occurring Adrb1A187V variant of the β1-adrenergic receptor, linked to short sleep in humans and mice. Editing reached up to 28.1% in the cortex six months after intracerebroventricular injection and increased excitability of β1-noradrenergic neurons. This enhanced wake-associated behaviors, including home cage activity, locomotion, exploration, and recognition memory, while reducing slow wave activity (SWA) during non-rapid eye movement (NREM) sleep indicating reduced build-up of sleep pressure during active phases. In a mouse model of Alzheimer's disease, Adrb1A187V installation restored physiological REM sleep and again reduced NREM sleep SWA following spontaneous activity. Together, these findings demonstrate the feasibility of prime editing for reprogramming genetic circuits in the brain and reveal beneficial effects of the Adrb1A187V variant on activity and sleep regulation.

DOI: https://doi.org/10.1038/s41467-025-65964-w