bims-micgli Biomed News
on Microglia
Issue of 2025–10–12
eight papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.
  2. Impact of APOE on cerebrovascular lipid profile in Alzheimer's disease.
  3. Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells.
  4. Early antiviral treatment following gammaherpesvirus-68 infection of the central nervous system prevents subsequent multiple sclerosis-like disease.
  5. Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes.
  6. A neuroimmune cerebral assembloid model to study the pathophysiology of familial Alzheimer's disease.
  7. Fate mapping of peripherally-derived macrophages after traumatic brain injury in mice reveals a long-lasting population with a distinct transcriptomic signature.
  8. Metabolic regulation of immune memory and function of microglia.
  1. Transl Psychiatry. 2025 Oct 06. 15(1): 375
    LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.
    Qiuyang Zhang, Hsuan Lo, Yue Song, Linjuan Feng, Hanlin You, Xiaochun Chen, Yanping Wang, Xiaodong Pan.
      Leucine-rich repeat kinase 2 (LRRK2), primarily expressed in microglia, is responsible for the modulation of innate immune responses and associated with various immunological disorders. Available evidence documents that though as the predominant etiological factor for familial Parkinson's disease, LRRK2 mutations rarely occur in Alzheimer's disease (AD) and that LRRK2 polymorphism is potentially associated with late-onset AD. However, the role of LRRK2 in AD immunopathogenesis remains unknown. In this study, we investigated the impact of LRRK2 deficiency on cognitive function, Aβ plaque accumulation, and plaque-associated neuropathology in AD mice. The results revealed that compared with the 5xFAD mice, the 8-month-old 5xFAD;LRRK2-/- mice reported improved learning and memory, reduced cerebral and hippocampal Aβ plaque burden, and decreased microglia and astrocytes within the central region of hippocampal Aβ plaques. The 5xFAD;LRRK2-/- mice also showed a decrease in several complement and proinflammatory cytokines in the brain, indicating an altered microglial phenotype. Furthermore, the absence of LRRK2 prevented synaptic loss and restored the disrupted equilibrium between excitatory and inhibitory synapses in the 5xFAD mice. These findings suggest that LRRK2 may play an essential role in Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brain of the 5xFAD mice and that a genomic transgene-blockade of LRRK2 may reprogram the microglial responsivity, thus mitigating the neuropathological and behavioral deficits in AD mice. The 5xFAD;LRRK2-/- mice reduced cognitive impairment in the Morris water maze test compared with the 5xFAD mice. The protective effect of LRRK2 inhibition is not dependent on the APP production process or Aβ degradation. Conversely, 5xFAD;LRRK2-/- mice enhanced microglial phagocytosis, reducing Aβ aggregation and glial activation. Additionally, compared with the 5xFAD, the 5xFAD;LRRK2-/- mice exhibited preserved synaptic structure, characterized by higher PSD95 expression, lower C1qa/C3 expression in both excitatory and inhibitory synapses, upregulated VGLUT1 expression, and downregulated VGAT expression.
    DOI:  https://doi.org/10.1038/s41398-025-03598-8
  2. Acta Neuropathol. 2025 Oct 08. 150(1): 39
    Impact of APOE on cerebrovascular lipid profile in Alzheimer's disease.
    Yasuteru Inoue, Hu Wang, Michael G Heckman, Yingxue Ren, Launia J White, Wenyan Lu, Pengjiao Wang, Julia Tcw, Shunsuke Koga, Alla Alnobani, Michael DeTure, Melissa E Murray, Ronald C Petersen, Dennis W Dickson, Guojun Bu, Xianlin Han, Takahisa Kanekiyo.
      Disturbances within the cerebrovascular system substantially contribute to the pathogenesis of age-related cognitive impairment and Alzheimer's disease (AD). Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-β (Aβ) in the leptomeningeal and cortical arteries and is highly prevalent in AD, affecting over 90% of cases. While the ε4 allele of apolipoprotein E (APOE) represents the strongest genetic risk factor for AD, it is also associated with cerebrovascular dysregulations. APOE plays a crucial role in brain lipid transport, particularly in the trafficking of cholesterol and phospholipids. Lipid metabolism is increasingly recognized as a critical factor in AD pathogenesis. However, the precise mechanism by which APOE influences cerebrovascular lipid signatures in AD brains remains unclear. In this study, we conducted non-targeted lipidomics on cerebral vessels isolated from the middle temporal cortex of 89 postmortem human AD brains, representing varying degrees of CAA and different APOE genotypes: APOE ε2/ε3 (N = 9), APOE ε2/ε4 (N = 14), APOE ε3/ε3 (N = 21), APOE ε3/ε4 (N = 23), and APOE ε4/ε4 (N = 22). Lipidomics detected 10 major lipid classes with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) being the most abundant lipid species. While we observed a positive association between age and total acyl-carnitine (CAR) levels (p = 0.0008), the levels of specific CAR subclasses were influenced by the APOE ε4 allele. Notably, APOE ε4 was associated with increased PE (p = 0.049) and decreased sphingomyelin (SM) levels (p = 0.028) in the cerebrovasculature. Furthermore, cerebrovascular Aβ40 and Aβ42 levels showed associations with sphingolipid levels including SM (p = 0.0079) and ceramide (CER) (p = 0.024). Weighted correlation network analysis revealed correlations between total tau and phosphorylated tau and lipid clusters enriched for PE plasmalogen and lysoglycerophospholipids. Taken together, our results suggest that cerebrovascular lipidomic profiles offer novel insights into the pathogenic mechanisms of AD, with specific lipid alterations potentially serving as biomarkers or therapeutic targets for AD.
    Keywords:  Alzheimer’s disease; Amyloid β; Apolipoprotein E; Cerebral amyloid angiopathy; Human induced pluripotent stem cell; Lipidomics; Tau; Vascular mural cells
    DOI:  https://doi.org/10.1007/s00401-025-02949-5
  3. Alzheimers Dement. 2025 Oct;21(10): e70772
    Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells.
    Logan M Bedford, Kaylee D Tutrow, Karly Hooper, Evan J Messenger, Melody Hernandez, Bruce T Lamb, Jason S Meyer, Timothy I Richardson, Stephanie J Bissel.
       INTRODUCTION: Variants of phospholipase C gamma 2 (PLCG2), a key microglial immune signaling protein, are genetically linked to Alzheimer's disease (AD) risk. Understanding how PLCG2 variants alter microglial function is critical for identifying mechanisms that drive neurodegeneration or resiliency in AD.
    METHODS: Induced pluripotent stem cell (iPSC) -derived microglia carrying the protective PLCG2P522R or risk-conferring PLCG2M28L variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function.
    RESULTS: Protective PLCG2P522R microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2M28L microglia shared similarities with PLCG2KO microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2P522R microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis.
    DISCUSSION: These findings demonstrate that PLCG2 variants drive distinct microglia transcriptomes that influence microglial functional responses that could contribute to AD risk and protection. Targeting PLCG2-mediated signaling may represent a powerful therapeutic strategy to modulate neuroinflammation.
    HIGHLIGHTS: The impact of Alzheimer's disease protective- and risk-associated variants of phospholipase C gamma 2 (PLCG2) on the transcriptome and function of induced pluripotent stem cell (iPSC) -derived microglia was investigated. PLCG2 risk variant microglia exhibited a basal transcriptional profile similar to PLCG2-deficient microglia but significantly different from isotype control and the transcriptionally similar PLCG2 protective variant microglia. PLCG2 risk variant and PLCG2-deficient microglia show decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2). The differential transcriptional pathways of protective and risk-associated PLCG2 variant microglia functionally affect proliferation, apoptosis, and immune response. Protective PLCG2 microglia show resilience to apoptosis and increased cytokine/chemokine secretion upon exposure to lipopolysaccharide (LPS).
    Keywords:  Alzheimer's disease; PLCG2; RNA: sequence analysis, RNA; apoptosis; cell death; cell proliferation; genetic predisposition to disease; genetic variants; induced pluripotent stem cells; microglia; phenotype
    DOI:  https://doi.org/10.1002/alz.70772
  4. J Neuroinflammation. 2025 Oct 08. 22(1): 228
    Early antiviral treatment following gammaherpesvirus-68 infection of the central nervous system prevents subsequent multiple sclerosis-like disease.
    Alexander Muselman, Sameera Kongara, Nathan Hsu, Asha Aggarwal, Joanna Yu, Jayakumar Rajadas, Edgar G Engleman.
       BACKGROUND: Growing evidence indicates that Epstein-Barr virus (EBV), a gammaherpesvirus, plays a central role in the pathogenesis of multiple sclerosis (MS). The presence of EBV-infected cells in the central nervous system (CNS) of MS patients, but not in neurologically healthy individuals, suggests that viral persistence in the CNS may drive MS. However, why there is such a long interval between initial infection and the development of disease is unknown.
    METHODS: To model the effects of EBV infection on the brain, we intracerebrally infected mice with murine gammaherpesvirus-68 (MHV68), a virus genetically related to EBV that causes transient pathology strikingly similar to that seen in humans after acute EBV infection. One month following MHV68 infection, we administered myelin oligodendrocyte glycoprotein (MOG) peptide to evaluate the effects of prior MHV68 infection on the response to an additional inflammatory stimulus of the CNS. Virus persistence, microglial activation and immune cell infiltration were evaluated over time using flow cytometry.
    RESULTS: Intracerebral MHV68 infection induced mild brain demyelination and ataxia, a common symptom of MS, that both quickly resolved. However, administration of MOG peptide one month later led to more severe brain demyelination and more sustained ataxia, suggesting that prior MHV68 infection sensitized the mice to a newly introduced immune stimulus. Further investigation revealed that following CNS infection, MHV68 persisted in microglia, where it induced a primed phenotype marked by elevated MHC-II expression and heightened immune reactivity for at least six months. Primed microglia displayed increases in the labile iron pool, and iron chelation reduced microglial priming. Early antiviral treatment during MHV68 infection completely prevented subsequent MOG-induced demyelinating disease.
    CONCLUSIONS: These findings support a two-step mechanism by which CNS infection with a gammaherpesvirus closely related to EBV sensitizes the host to a second unrelated immune stimulus that triggers MS-like disease manifestations. Chronic priming of microglia resulting from the initial infection contributes to this process, and prevention of such priming with early antiviral treatment also prevents neuropathology following the second stimulus. EBV infection may similarly sensitize humans to a second stimulus and, if so, treatment of acute EBV infection may avert subsequent MS development.
    Keywords:  Epstein-Barr virus; Immune priming; Iron; Metabolism; Microglia; Multiple sclerosis; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-025-03547-8
  5. Alzheimers Dement. 2025 Oct;21(10): e70791
    Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes.
    Md Mamun Al-Amin, Byungwook Kim, Hande Karahan, Mason D Tate, Sam P Walsh, Shweta S Puntambekar, Stephanie J Bissel, Bruce T Lamb, Nian Wang, Jungsu Kim.
       INTRODUCTION: The ε4 allele of the apolipoprotein E (APOE) gene is a risk factor for the development of Alzheimer's disease (AD). APOE4 isoform is associated with increased white matter lesions in humans. To identify the underlying mechanisms of white matter impairment associated with APOE4, we investigated the effects of APOE4 and APOE3 on multiple readouts of the white matter microstructural integrity.
    METHODS: Using magnetic resonance imaging and immunohistochemistry approaches, we analyzed white matter tracts in 5xFAD mice expressing APOE3 (5xFAD;APOE3) or APOE4 (5xFAD;APOE4).
    RESULTS: APOE4 significantly decreased fractional anisotropy, axial diffusivity, and neurite density index, while increasing radial diffusivity and isotropic volume fraction within major white matter tracts. Myelination was reduced in the corpus callosum of 5xFAD;APOE4 mice. Mechanistically, APOE4 reduced populations of mature and actively myelinating oligodendrocytes.
    DISCUSSION: Our results suggest that a decrease in the number of actively myelinating oligodendrocytes may explain myelin loss, leading to white matter impairments.
    HIGHLIGHTS: A robust neurite orientation dispersion and density imaging (NODDI) approach to study the effect of apolipoprotein E (APOE) isoforms on the white matter in 5xFAD mice. APOE4 reduces neurite density and increases water accumulation in the white matter. APOE4 disrupts structural connectivity and reduces the betweenness centrality. APOE4 decreases the number of actively myelinating oligodendrocytes. A reduction in myelinating oligodendrocyte populations may lead to myelin loss.
    Keywords:  Alzheimer's disease; apolipoprotein E4; myelin; oligodendrocyte; white matter
    DOI:  https://doi.org/10.1002/alz.70791
  6. J Neuroinflammation. 2025 Oct 08. 22(1): 227
    A neuroimmune cerebral assembloid model to study the pathophysiology of familial Alzheimer's disease.
    Andrea Becerra-Calixto, Anik Banerjee, Huihui Fan, Chunfeng Tan, Eunyoung Lee, Louise D McCullough, Juneyoung Lee.
      Alzheimer's disease (AD) is the leading cause of dementia globally. The accumulation of amyloid and tau proteins, neuronal cell death and neuroinflammation are seen with AD progression, resulting in memory and cognitive impairment. Microglia are crucial for AD progression as they engage with neural cells and protein aggregates to regulate amyloid pathology and neuroinflammation. Recent studies indicate that microglia contribute to the propagation of amyloid beta (Aβ) via their immunomodulatory functions including Aβ phagocytosis and inflammatory cytokine production. Three-dimensional cell culture techniques provide the opportunity to study pathophysiological changes in AD in human-derived samples that are difficult to recapitulate in animal models (e.g., transgenic mice). However, these models often lack immune cells such as microglia, which play a critical role in AD pathophysiology. In this study, we developed a neuroimmune assembloid model by integrating cerebral organoids (COs) with induced microglia-like cells (iMGs) derived from human induced pluripotent stem cells from familial AD patient with PSEN2 mutation. After 120 days in culture, we found that iMGs were successfully integrated within the COs. Interestingly, our assembloids displayed histological, functional and transcriptional features of the pro-inflammatory environment seen in AD, including amyloid plaque-like and neurofibrillary tangle-like structures, reduced microglial phagocytic capability, and enhanced neuroinflammatory and apoptotic gene expression. In conclusion, our neuroimmune assembloid model effectively replicates the inflammatory phenotype and amyloid pathology seen in AD.
    Keywords:  Alzheimer’s disease; Amyloid beta; Assembloids; Cerebral organoids; Microglia; Neuroinflammation; Stem cells
    DOI:  https://doi.org/10.1186/s12974-025-03544-x
  7. Nat Commun. 2025 Oct 07. 16(1): 8898
    Fate mapping of peripherally-derived macrophages after traumatic brain injury in mice reveals a long-lasting population with a distinct transcriptomic signature.
    Maria Serena Paladini, Benjamin A Yang, Kristof A Torkenczy, Elma S Frias, Xi Feng, Karen Krukowski, Rene Sit, Maurizio Morri, Wendy Lam, Valentina Pedoia, Stefka Tyanova, Marco Colonna, Amber L Nolan, Susanna Rosi.
      Traumatic brain injury (TBI) is an environmental risk factor for dementia and long-term neurological deficits, posing a significant public health challenge. TBI-induced neuroinflammation involves both brain-resident microglia and peripheral monocyte-derived macrophages (MDMs). Previous research has shown that MDMs contribute to the development of long-term memory deficits, yet their long-term behavior following brain infiltration remains unclear. To address this, our study uses two complementary fate-mapping mouse lines, CCR2-creERT2 and Ms4a3-cre, for precise and lasting tracking of MDMs in vivo. Here we show that MDMs persist in the brain for at least 8 months post-TBI in both male and female mice. MDMs retain phagocytic activity for at least 30 days post-TBI, remain transcriptionally distinct from microglia, and display a gene expression profile associated with aging and disease. Moreover, we identify a core transcriptomic signature of MDMs shared across various mouse models and brain perturbations, which is also enriched in the brain myeloid cells of male subjects with TBI and Alzheimer's disease patients. These findings enhance our understanding of MDMs' dynamics after TBI and inform future targeted myeloid-based therapies.
    DOI:  https://doi.org/10.1038/s41467-025-63952-8
  8. Elife. 2025 Oct 10. pii: e107552. [Epub ahead of print]14
    Metabolic regulation of immune memory and function of microglia.
    Nikolaos Nirakis, Sofia Dimothyra, Eleftheria Karadima, Vasileia Ismini Alexaki.
      Innate immune cells possess memory-like properties. Exposure to infections or sterile inflammation can prime them, leading to either exacerbated inflammatory responses, a process called trained immunity, or reduced responsiveness to pro-inflammatory signals, a process termed immune tolerance. Microglia, the resident innate immune cells of the central nervous system, are central players in neurodegenerative diseases. Characterizing trained immunity and tolerance in microglia is necessary for a better understanding of neurodegenerative diseases. Cell metabolic processes orchestrate microglia inflammatory responses and promote epigenetic changes shaping immune memory in microglia. Here, we review current knowledge on the role of cell metabolic pathways in microglia innate immune memory formation, focusing on glucose, glutamine, and lipid metabolism. Moreover, we address the significance of microglial immune memory in disease pathology and discuss the potential of therapeutic targeting of cell metabolic pathways in neurodegenerative disorders.
    Keywords:  cell metabolism; immunology; inflammation; microglia; tolerance; training
    DOI:  https://doi.org/10.7554/eLife.107552
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