bims-micgli 2025-11-30 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–11–30
38 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.
The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.
Microglial Nrf2 Functions as a Cell-Autonomous Regulator of Neuroinflammation and Trained Immunity in the Aging Brain.
Low-Intensity Pulsed Ultrasound Attenuates Neuroinflammation and Preserves Synaptic Integrity by Modulating Microglial Polarization Through the MAPK-NF-κB Pathway After Traumatic Brain Injury.
Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals key associations with AD pathology.
Neuronal GSK3β Protects Against Amyloid Pathology by Regulating APP Degradation.
Neuroimaging Compendium of Microglia, Amyloid, Tau, and Neurodegeneration Across Clinical Variants of Alzheimer Disease.
Phagocytes as Plaque Catalysts: Human Macrophages Actively Generate Pathogenic Aβ42 Fibrils with Seeding and Cross-Seeding Potency.
Microglial phagocytosis in Alzheimer disease.
Investigation of Neurons and Microglia from APOE3 Induced Pluripotent Stem Cells using Data-Independent Acquisitions on a ZenoTOF 7600.
Microglial plasticity across development mediates infantile amnesia.
Functional Genomic Profiling of Schizophrenia-Associated Genes Reveals Key Microglial Regulators.
IL-12 ameliorates diabetic retinal neurodegeneration by activating microglial phagocytosis via the TREM2/DAP12 pathway.
Mitochondrial bioenergetic signatures differentiate asymptomatic from symptomatic Alzheimer's disease.
Lipidomic Signatures in Microglial Extracellular Vesicles During Acute Inflammation: A Gateway to Neurological Biomarkers.
A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes.
Core Activation Program and Selective Regional Responsiveness of Microglia in Aging and Parabiosis.
Transcriptomic profiling of the middle temporal gyrus reveals differential glial/neuronal dysregulation across Alzheimer's disease and aging.
The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies.
Mapping cross-domain drivers of Alzheimer's disease risk through integrated network analysis.
APOE4-Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation a preclinical Alzheimer's disease model.
Transient overexpression of hPKM2 in porcine cardiomyocytes prevents heart failure after myocardial infarction.
Brain-derived extracellular vesicles circUsp32 polarized macrophages causing acute kidney injury after traumatic brain injury.
Development and Validation of an ICP-MS/MS Method for the Multielemental Analysis of Cerebrospinal Fluid, Examination of Alzheimer's Disease Samples.
"Rewiring brain immunity: targeting microglial metabolism for neuroprotection in neurodegenerative disorders".
White Blood Cells in Neurodegenerative Diseases in the Context of Neuroinflammation.
The relationship between amyloid-β peptide spectrum and the spastic paraparesis phenotype in autosomal dominant Alzheimer's disease.
Cellular and Extracellular MicroRNA Dysregulation in LRRK2-Linked Parkinson's Disease.
Altered Lipid Metabolism in the Vaginal Wall of Women With Pelvic Organ Prolapse: A Targeted Lipidomics Study.
Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination.
Alzheimer's Tau seeds-induced pathology enhances hippocampal extracellular diffusion.
NRF2 activation by CDDO-Im regulates inflammatory and autophagy pathways in human microglial cells.
Ablation of microglial estrogen receptor alpha predisposes to diet-induced obesity in male mice.
Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling.
Spatiotemporal patterns differentiate hippocampal sharp-wave ripples from interictal epileptiform discharges in mice and humans.
Every-Other-Day Feeding Prevents the Loss of Parvalbumin-Expressing Neurons in the Cerebral Cortex of Female 5xFAD Mice.
Protocol for in vitro phagocytosis assay for primary mouse microglia and human embryonic stem cell-derived microglia.
Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer's disease.

Alzheimers Dement. 2025 Nov;21(11): e70943

Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.

Aman Mangalmurti, Kristine E Zengeler, Ava Hollis, Emily Golden, Gabrielle Riddlemoser, John R Lukens.

   INTRODUCTION: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is known about the role that microglial CLEC7A signaling plays in AD-related pathogenesis.
METHODS: We utilized an inducible, central nervous system (CNS) macrophage-specific knockout of Clec7a to evaluate the role of CLEC7A in the 5xFAD mouse model of AD at 5 months of age. We used immunofluorescence microscopy, single-nuclei RNA sequencing, along with biochemical assays, to evaluate plaque burden, microglial activity, and neuronal health.
RESULTS: CNS macrophage-targeted deletion of CLEC7A in 5xFAD mice led to a twofold increase in plaque burden, exacerbated neuritic dystrophy, and altered the expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia acquisition.
DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies for treatment of AD.
HIGHLIGHTS: Conditional loss of CLEC7A in central nervous system (CNS) macrophages of 5xFAD mice results in increased amyloid beta deposition. Loss of CLEC7A does not alter the disease-associated microglia transcriptional program or affect the recruitment of microglia to plaque surfaces. Exacerbation of amyloid deposition with loss of CNS-macrophage CLEC7A is associated with worsened neuronal health highlighted by increased neuritic dystrophy.

Keywords:  Alzheimer's disease; CLEC7A; amyloid beta; amyloidosis; innate immunity; microglia; neurodegenerative disease; neuroimmunology

DOI:  https://doi.org/10.1002/alz.70943
Nat Neurosci. 2025 Nov 24.

The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.

Giulia Albertini, Magdalena Zielonka, Marie-Lynn Cuypers, An Snellinx, Ciana Xu, Suresh Poovathingal, Marta Wojno, Kristofer Davie, Veerle van Lieshout, Katleen Craessaerts, Leen Wolfs, Emanuela Pasciuto, Tom Jaspers, Katrien Horré, Lurgarde Serneels, Mark Fiers, Maarten Dewilde, Bart De Strooper.

Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.

DOI: https://doi.org/10.1038/s41593-025-02125-8
FASEB J. 2025 Nov 30. 39(22): e71244

Microglial Nrf2 Functions as a Cell-Autonomous Regulator of Neuroinflammation and Trained Immunity in the Aging Brain.

Hallel C Paraiso, Jui-Hung Jimmy Yen, Barbara A Scofield, Ping-Chang Kuo, Fen-Lei Chang, I-Chen Ivorine Yu.

Aging is the primary risk factor for Alzheimer's disease (AD) and related dementias, with chronic neuroinflammation contributing to disease progression. Microglia, the brain's resident immune cells, undergo age-associated changes that disrupt neuroimmune homeostasis and exacerbate neuroinflammation. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), a master regulator of cellular stress responses, has an undefined role in microglial aging. We demonstrate that Nrf2 mRNA expression and protein decline in aged microglia, coinciding with increased neuroinflammation and antigen presentation. Global Nrf2-deficient (Nrf2-/-) mice exhibit amplified microglial activation, elevated MHC class II-related CD74 expression, and enhanced infiltration of peripheral CD4+ T cells into the brain. Nrf2-/- microglia adopt a disease-associated microglia (DAM)-like phenotype, characterized by upregulated activation markers and transcriptional reprogramming. Functionally, Nrf2 loss impairs motor learning and cognitive performance in middle-aged mice. To dissect the role of microglial Nrf2, we generated microglia-specific Nrf2 knockout (MG-Nrf2-KO) mice using a Cx3cr1-CreERT2 system. MG-Nrf2-KO mice exhibit exaggerated microglial immune training characterized by elevated brain TNFα and IL-1β production upon secondary LPS challenge, despite preserved peripheral immune tolerance. The heightened training response is accompanied by reduced IL-10 expression in MG-Nrf2-KO brains, indicating impaired anti-inflammatory counter-regulation. Ex vivo restimulation confirms that Nrf2-deficient microglia intrinsically produce elevated pro-IL-1β protein upon rechallenge, establishing Nrf2 as a cell-autonomous regulator of microglial immune memory. These findings identify Nrf2 as an intrinsic regulator of microglial immune memory and neuroinflammatory restraint. Modulating Nrf2 signaling in microglia may offer a therapeutic strategy to mitigate chronic neuroinflammation and cognitive decline in aging and neurodegeneration.

DOI: https://doi.org/10.1096/fj.202501457RR
FASEB J. 2025 Dec 15. 39(23): e71246

Low-Intensity Pulsed Ultrasound Attenuates Neuroinflammation and Preserves Synaptic Integrity by Modulating Microglial Polarization Through the MAPK-NF-κB Pathway After Traumatic Brain Injury.

Nai-Jie Hsiau, Chun-Yen Lee, Chia-Hua Ke, Chun-Hu Wu, Szu-Fu Chen, Feng-Yi Yang.

  Traumatic brain injury (TBI) triggers a pronounced inflammatory response in the central nervous system that significantly contributes to secondary damage and long-term neurological deficits. Microglia, the resident immune cells of the brain, are key mediators of this response; however, their activation after TBI often shifts toward a proinflammatory (M1) phenotype, exacerbating tissue injury and impairing repair. This study investigated (1) the therapeutic potential of low-intensity pulsed ultrasound (LIPUS) in modulating microglial activation and polarization, and (2) its effects on inflammatory pathways, cytokine release, synaptic integrity, and functional recovery after TBI in mice. Using BV2 and primary microglia as in vitro models, we further examined the effects of LIPUS on inflammatory responses and key signaling pathways in interferon-gamma (IFN-γ)-induced microglial activation. In a controlled cortical impact mouse model, LIPUS significantly reduced microglial activation and neuroinflammation, decreased M1 polarization (CD16) while enhancing M2 polarization (CD206), preserved hippocampal synaptic integrity, and improved long-term neurological and cognitive outcomes, even when administered up to 6 h post-injury. In vitro, LIPUS attenuated IFN-γ-induced microglial activation, suppressed proinflammatory cytokine release, and inhibited activation of the mitogen-activated protein kinase-nuclear factor-κB pathway. Together, these findings demonstrate that LIPUS promotes a reparative microglial phenotype, maintains synaptic and neuronal function, and facilitates recovery after TBI, supporting its potential as a noninvasive therapeutic strategy with translational relevance.

Keywords:  M1‐polarized microglia; M2‐polarized microglia; microglia; neuroinflammation; traumatic brain injury; ultrasound

DOI:  https://doi.org/10.1096/fj.202502379R
Nat Commun. 2025 Nov 24. 16(1): 10395

Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals key associations with AD pathology.

Pallavi Gaur, Julien Bryois, Daniela Calini, Lynette C Foo, Jeroen J M Hoozemans, Archana Yadav, Dheeraj Malhotra, Vilas Menon.

Alzheimer's disease, the leading cause of dementia in the elderly, is a neurodegenerative disorder that has been studied to uncover therapeutic pathways through its molecular and cellular hallmarks. Here, we present a comprehensive investigation of cellular heterogeneity from the temporal cortex region of 40 individuals, comprising healthy donors and individuals with differing AD pathology. Using single-nucleus transcriptomic analysis of 430,271 nuclei from both gray and white matter of these individuals, we identified cell type-specific subclusters in both neuronal and glial cell types with varying degrees of association with AD pathology. We extended this analysis by performing multiplexed in situ hybridization using the CARTANA platform, capturing 155 genes in 13 individuals with differing tau pathology. We not only replicated snRNA data key findings from our spatial data analysis but also identified a set of cell type-specific genes that show selective enrichment or depletion near pathological inclusions.

DOI: https://doi.org/10.1038/s41467-025-65350-6
FASEB J. 2025 Nov 30. 39(22): e71267

Neuronal GSK3β Protects Against Amyloid Pathology by Regulating APP Degradation.

Yizhi Zhang, Yajie Zhang, Chenyi Ge, Yang Liu, Zhiye Wang, Guiquan Chen.

  Glycogen synthase kinase 3β (GSK3β) exhibits dysregulated activity in Alzheimer's disease (AD), yet its cell type-specific roles in driving disease pathogenesis remain poorly understood. To explore the neuronal role of GSK3β in β-amyloid (Aβ) pathogenesis, we conditionally deleted Gsk3β in 5 × FAD mice using CaMKIIα-Cre-mediated recombination. Neuronal Gsk3β deletion exacerbated AD pathology, including increased Aβ deposition, pronounced gliosis, and enhanced neuroinflammatory responses. Loss of GSK3β impaired amyloid precursor protein (APP) degradation, leading to its accumulation and subsequent Aβ overproduction. These findings identify neuronal GSK3β as a critical modulator of APP turnover and Aβ pathology, revealing a protective role against AD progression. These findings suggest that broad inhibition of GSK3β may not be an optimal therapeutic strategy for AD, highlighting the importance of cell type-specific targeting.

Keywords:  Alzheimer's disease; GSK3β; amyloid precursor protein; neuroinflammation; protein degradation

DOI:  https://doi.org/10.1096/fj.202502996R
Alzheimer Dis Assoc Disord. 2025 Oct-Dec 01;39(4):39(4): 315-319

Neuroimaging Compendium of Microglia, Amyloid, Tau, and Neurodegeneration Across Clinical Variants of Alzheimer Disease.

Hannah Houlihan, Diana Guzman, Anna Smith, Thairi Sanchez, Aubrey Johnson, William C Kreisl, Stephanie Cosentino, James M Noble, Patrick Lao.

  Alzheimer disease and its clinical variants have characteristic spatial and temporal progression patterns of amyloid and tau driving symptomatology, but the distribution of microglia density, as measured by 18kDa translocator protein (TSPO) PET, is unknown. Baseline TSPO, amyloid, and tau PET as well as T1 MRI from the longitudinal imaging of microglial activation in different clinical variants of Alzheimer disease study were adjusted for age, sex, body mass index, APOE4 status, TSPO genotype, and intracranial total volume. Imaging outcomes were standardized against controls, visualized across the brain, and placed along a pseudo-longitudinal timeline using disease duration. Microglia density follows the spatial distribution of tau in amyloid-positive individuals and that of neurodegeneration in amyloid-negative individuals. The magnitude, location, and timing of elevated microglia density relative to amyloid, tau, and neurodegeneration is specific to different clinical subtypes of Alzheimer disease.

Keywords:  amyloid; differential diagnosis; microglia; neurodegeneration; tau

DOI:  https://doi.org/10.1097/WAD.0000000000000707
bioRxiv. 2025 Oct 12. pii: 2025.10.11.681781. [Epub ahead of print]

Phagocytes as Plaque Catalysts: Human Macrophages Actively Generate Pathogenic Aβ42 Fibrils with Seeding and Cross-Seeding Potency.

Katerina Konstantoulea, Meine Ramakers, Sarah C Borrie, Dries T'syen, Daan Moechars, Malgorzata A Sliwinska, Brajabandhu Pradhan, Giulia Albertini, Grigoria Tsaka, Bert Houben, Mark Fiers, Maarten Dewilde, Dietmar Rudolf Thal, Michael Willem, Jonas J Neher, Bart De Strooper, Frederic Rousseau, Joost Schymkowitz.

  The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells-including differentiated THP-1 macrophages and iPSC-derived microglia-are not merely passive responders but active producers of extracellular, seeding-competent Aβ42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These cell-generated aggregates differ structurally and functionally from synthetic fibrils, exhibiting heightened seeding activity and the ability to cross-seed tau aggregation, a key driver of AD progression. Notably, Aβ42 fibril formation in this system requires active cellular processes and is exacerbated by loss of TREM2, a major AD risk gene. Transcriptomic profiling reveals an early inflammatory response resembling microglial states observed in human AD models, positioning this system as a tractable, human-relevant platform to dissect the interplay between Aβ aggregation, innate immunity, and genetic susceptibility. Our findings suggest that macrophages and microglia play a dual role in AD, acting both as responders and inadvertent catalysts of pathogenic amyloid formation, with implications for early therapeutic intervention.

Keywords:  Alzheimer’s disease; Amyloid aggregation; Amyloid beta (Aβ42); Inflammation; Microglial response; Neurodegeneration; Seeding activity; THP-1 macrophages; TREM2 dysfunction; n vitro model

DOI:  https://doi.org/10.1101/2025.10.11.681781
Nat Rev Neurol. 2025 Nov 28.

Microglial phagocytosis in Alzheimer disease.

Guy C Brown, Peter St George-Hyslop, Rosa C Paolicelli, Greg Lemke.

Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD - anti-Aβ antibodies - work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complement, P2Y6 receptor and TREM2. However, the roles of microglial phagocytosis in AD are complex and multifaceted, and improved treatments are likely to require a deeper understanding of these roles.

DOI: https://doi.org/10.1038/s41582-025-01162-y
bioRxiv. 2025 Nov 04. pii: 2025.11.02.686128. [Epub ahead of print]

Investigation of Neurons and Microglia from APOE3 Induced Pluripotent Stem Cells using Data-Independent Acquisitions on a ZenoTOF 7600.

Jordan B Burton, Tyne McHugh, Charles A Schurman, Joanna Bons, Maria Sanchez, Lisa M Ellerby, Birgit Schilling.

Induced pluripotent stem cell (iPSC)-derived neurons and microglia are valuable human models for studying neurodegenerative diseases. Specifically, the apolipoprotein E4 ( APOE4 ) gene is a major genetic risk factor for late-onset Alzheimer's disease. Apolipoprotein E ( APOE ) alleles E2, E3 and E4 can be beneficial, neutral, or increase the risk of Alzheimer's disease (AD). Here, we developed a proteomic workflow using data-independent acquisitions to provide a quantitative mass spectrometric proteome analysis, and proteomic screening assays for brain-specific cell types derived from iPSC. Protein groups were quantified in APOE3 neurons and microglia, respectively, with ∼80% overlap. Cell type-specific markers and enriched pathways reflected the specialized functions of each cell type, such as synaptic signaling in neurons and immune and inflammatory responses in microglia. The neuron-specific markers included proteins APP, CALB1, CALB2, DLGs, GAP43, NEFL, MAPs; while microglial markers included proteins AIF1, CDs, MMP9, and ITGAM. Ultimately, the combination of robust iPSC differentiation and sensitive proteomic screening assays described here provides a valuable platform for probing the cellular mechanisms underlying neurological disorders.
Significance: The quantification of dysregulated proteins and pathways in patient-derived neurons and microglia can provide insights into disease etiology and progression. More broadly, this DIA approach enables deep proteome profiling of unique iPSC-derived cell models, increasing their utility for investigating disease biology and therapeutic development. We focused on iPSC models from two important cell types of the brain, excitatory neurons and microglia. We integrated the proteomes of these two cell types. These tools provide robust biological and mass spectrometric screening tools for future therapeutic interventions using disease-relevant human brain cell types or brain organoid models.
Graphical abstract:
Highlights: Presentation of a proteomic workflow using data-independent acquisitions to monitor and screen proteomes of iPSC-derived brain cell types.Quick MS Assays to determine protein profiles of iPSC-derived neurons and microglia. Characterization of different cell type proteomes from APOE3 iPSCs. Revealing of neuron-specific markers and microglia-specific markers by mass spectrometry.Step-by-step instructions for the set-up of the DIA-MS assays.

DOI: https://doi.org/10.1101/2025.11.02.686128
bioRxiv. 2025 Oct 17. pii: 2025.10.17.683060. [Epub ahead of print]

Microglial plasticity across development mediates infantile amnesia.

Erika Stewart, Louisa G Zielke, Gabrielle Guillaume, Anne De Boer, Sarah D Power, Tomás J Ryan.

Infantile amnesia, the inability to recall episodic memories formed during early childhood, is a hallmark of postnatal brain development. Yet the underlying mechanisms remain poorly understood. This work aimed to gain a better mechanistic understanding of infantile amnesia. Microglia, specialized macrophages of the central nervous system, are known to play an important role in synaptic refinement during postnatal development and have recently been implicated in memory related functions. Here, we identified microglia as key regulators of memory accessibility in infancy. We profiled dynamic changes in microglial morphology across the postnatal window that parallelled the onset of infantile forgetting. We found that pharmacological inhibition of microglial activity during a specific postnatal window prevents infantile amnesia for a contextual fear memory, implicating microglia as active modulators of infant memory persistence. Using activity-dependent tagging of infant encoded engram cells, we demonstrated that microglial inhibition alters engram size and engram reactivation in the amygdala and results in changes in microglia-engram cell interactions. Furthermore, we characterized a relationship between microglial dysfunction and the lack of infantile amnesia in maternal immune activation offspring. Together, these findings reveal a novel role for microglia in regulating infant memory retrieval and suggest that microglial dysfunction may contribute to altered memory trajectories in neurodevelopmental disorders.

DOI: https://doi.org/10.1101/2025.10.17.683060
bioRxiv. 2025 Nov 14. pii: 2025.11.14.688490. [Epub ahead of print]

Functional Genomic Profiling of Schizophrenia-Associated Genes Reveals Key Microglial Regulators.

Joy E Horng, Liam T McCrea, Rebecca E Batorsky, Joshua J Bowen, Camilla Boschian, Yoonjae Song, Roy H Perlis, Steven D Sheridan.

Microglia are increasingly recognized as key regulators of neural circuit development and putative contributors to the pathophysiology of neuropsychiatric disorders such as schizophrenia (SCZ). However, the functional impact of SCZ-associated genes in microglia remains largely unexplored. Here, we performed an arrayed CRISPR targeting screen of 30 schizophrenia-associated genes predicted to be differentially expressed in human microglia-like cells. Target genes were prioritized based on post-mortem transcriptomic relevance and predicted ontology-based roles in phagocytosis pathways. We quantified phagocytic activity and morphological changes following gene targeting using high-content confocal imaging. Key targets, including CYFIP1, MSR1, TREM2, SYK, ITGB2 , ITGAM and IRF8 , modulated phagocytosis and altered morphological properties consistent with activation states, validating their functional roles in microglia. To elucidate transcriptional impact, we further applied a multiplexed RNA sequencing platform across gene targets. These analyses revealed gene-specific transcriptional signatures, implicating divergent pathways related to phagocytic, activation, cytoskeletal, and lysosomal function. Together, these findings demonstrate the utility of CRISPR-based functional genomics in characterizing microglia function and identifying new target genes and mechanisms that may underlie their contributions to schizophrenia pathophysiology.

DOI: https://doi.org/10.1101/2025.11.14.688490
Mol Neurobiol. 2025 Nov 29. 63(1): 215

IL-12 ameliorates diabetic retinal neurodegeneration by activating microglial phagocytosis via the TREM2/DAP12 pathway.

Wanyi Fang, Shanshan Liu, Yifei Wu, Ting Chen, Xiaohe Lu, Hui Chen.

  Diabetic retinopathy (DR) is a common neurovascular complication of diabetes and a leading cause of vision loss in the advanced stages. Identifying therapeutic targets to prevent early progression of DR is critical for preserving visual function. Interleukin-12 (IL-12) has emerged as a potential therapeutic agent for early-stage diabetic retinal neurodegeneration. In this study, diabetic mouse models were established, followed by intravitreal injection of IL-12 to evaluate its effects using hematoxylin and eosin staining and RNA sequencing. IL-12 treatment partially prevented the thinning of the nerve fiber layer, ganglion cell layer, and total retina. Bioinformatics analysis of RNA sequencing data revealed enrichment of microglial signatures and enhanced phagocytic function. Western blotting analysis showed that IL-12 promoted the phosphorylation of signal transducer and activator of transcription 4 (STAT4) in microglia. Bioinformatics and quantitative reverse transcription polymerase chain reaction analyses demonstrated that STAT4 activation upregulated the transcription of phagocytosis-related genes, including triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12). In vitro and in vivo experiments confirmed that IL-12 upregulates the TREM2/DAP12 signaling pathway on the microglial membrane, enhancing microglial proliferation and phagocytic activity under high-glucose conditions. These findings indicated that IL-12 mitigates early neural injury in DR by promoting microglial phagocytosis through the upregulation of TREM2/DAP12.

Keywords:  DAP12; Interleukin-12; Microglia; Retina; TREM2

DOI:  https://doi.org/10.1007/s12035-025-05512-1
bioRxiv. 2025 Nov 06. pii: 2025.11.04.686626. [Epub ahead of print]

Mitochondrial bioenergetic signatures differentiate asymptomatic from symptomatic Alzheimer's disease.

Purba Mandal, Eugenia Trushina, Matthias Arnold, Rima Kaddurah-Daouk, Priyanka Baloni.

Asymptomatic Alzheimer's disease (AsymAD) refers to individuals who, despite exhibiting amyloid-β plaques and tau pathology comparable to Alzheimer's disease (AD), maintain cognitive performance similar to cognitively normal individuals. The resilience mechanism in these AsymAD individual remains understudied. We performed a systematic analysis comparing AsymAD and AD across multiple cohorts (ROSMAP, Banner and Mount Sinai), brain regions (BA6, BA9, BA36 and BA37) and neuronal and glial cell types using proteomics and transcriptomics data. AsymAD brains exhibited preserved mitochondrial bioenergetics, characterized by enhanced oxidative phosphorylation (OXPHOS), electron transport chain (ETC) activity, fatty acid and lipid metabolism, and branched-chain amino acid (BCAA) utilization. Pathways regulating mitochondrial complex biogenesis and calcium homeostasis were also upregulated. Key mitochondrial proteins such as MRPL47, CPT2, BCAT2, and IDH2, were consistently upregulated in AsymAD, whereas MACROD1 was downregulated. At the cellular level, excitatory neurons, including superficial, mid-layer, and deep-layer subtypes, exhibited the most preserved mitochondrial function, whereas vulnerable inhibitory subtypes, including PVALB and SST neurons, showed increased cellular abundance and bioenergetic activity. In contrast, microglia and oligodendrocytes proportions were reduced in AsymAD relative to AD. Our findings identify preserved mitochondrial bioenergetics as a defining feature of resilience in AD and suggest that enhancing NADH metabolism via NAD+ precursor-based interventions may potentially help in maintaining cognitive function despite amyloid and tau pathology.

DOI: https://doi.org/10.1101/2025.11.04.686626
J Neurochem. 2025 Nov;169(11): e70309

Lipidomic Signatures in Microglial Extracellular Vesicles During Acute Inflammation: A Gateway to Neurological Biomarkers.

Nikita Ollen-Bittle, Wenxuan Wang, Kimberly Molina Bean, Shuang Zhao, Adriana Zardini Buzatto, Yifei Dong, Liang Li, Shawn N Whitehead.

  Extracellular vesicles (EVs) are membrane-bound vesicles released from all cells throughout the body, including the central nervous system, and are known to carry both membrane-bound proteins and cargo reflective of their cell of origin. EVs show promise as neurological disease biomarkers due to their molecular makeup reflecting their parent-cell composition signature and due to their ability to cross the blood-brain barrier. To date, the vast majority of research in this field has explored the protein profiles of EVs; however, lipids play an important role not only in the formation of EVs, but also in mediating cellular function and the pathological progression of many neurodegenerative conditions. Herein, we take a critical first step in determining the potential utility of EV lipids as biomarkers in neurological disease. In vitro we exposed BV-2 microglia to either control media or media containing lipopolysaccharides (LPS), a known pro-inflammatory stimulus, for 24 h then isolated both the cells and their EVs and performed LC-MS/MS. For the first time, we reveal distinct lipidomic changes can differentiate resting versus pro-inflammatory microglia and their EVs, while distinct lipids are preserved between EVs and their parent cell. Moreover, we add to current literature by demonstrating acute pro-inflammatory activation of microglia results in the activation and suppression of distinct lipidomic pathways. Finally, we demonstrate that analysis of lipid-based relationships between parent cells and their EVs may be a useful tool to infer cellular function. This study is the first of its kind to demonstrate that lipidomic analysis can not only differentiate the functional state of cells in vitro but can also differentiate their EVs. We lay the first brick in a foundation to support future research into EV lipids as novel and exciting biomarker candidates in neurological disease.

Keywords:  LC‐MS/MS; biomarkers; extracellular vesicles; lipidomics; lipids; microglia; neurological disease

DOI:  https://doi.org/10.1111/jnc.70309
Nat Immunol. 2025 Nov 28.

A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes.

Neetu Srivastava, Anthony N Vomund, Rongzhen Yu, Orion J Peterson, Yuqing Yang, David P Turicek, Omar Abousaway, Tiandao Li, Lisa Kain, Pamela Stone, Aisha Ansar, Cristina C Clement, Siddhartha Sharma, Rima Melhem, Bo Zhang, Chang Liu, Alok V Joglekar, Hao Hu, Chyi-Song Hsieh, Laura Campisi, Laura Santambrogio, Luc Teyton, Emil R Unanue, Ana Maria Arbelaez, Cheryl F Lichti, Xiaoxiao Wan.

The antigenic landscape of autoimmune diabetes reflects a failure to preserve self-tolerance, yet how novel neoantigens emerge in humans remains incompletely understood. Here we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes. We uncovered a Cys→Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin at the single-residue level. This transformation, which we call C19S, arises from oxidative remodeling of insulin in stressed pancreatic islets and also occurs in cytokine-activated antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation. Despite involving just one amino acid, C19S is recognized by HLA-DQ8-restricted, register-specific CD4+ T cells that expand at diabetes onset. These neoepitope-specific CD4+ T cells lack regulatory potential but acquire a poised central memory phenotype that persists throughout disease progression. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes.

DOI: https://doi.org/10.1038/s41590-025-02343-z
bioRxiv. 2025 Oct 31. pii: 2025.10.29.685417. [Epub ahead of print]

Core Activation Program and Selective Regional Responsiveness of Microglia in Aging and Parabiosis.

Huma Naz, Robert Pálovics, Shinnosuke Yamada, Nannan Lu, Tony Wyss-Coray, Qingyun Li, Guoyan Zhao.

Aging is associated with immune dysregulation in brain and is the biggest risk factor for many neurodegenerative diseases whereas rejuvenation interventions can mediate beneficial effects. Microglia are considered as a major player in the development of neurodegenerative disease yet, the molecular changes underlying brain aging and rejuvenation remain poorly understood at the single cell level. We identified and benchmarked several reproducible microglial states and a core set of genes leading to microglia activation in the mice brain. We investigated microglial heterogeneity and studied the impact of aging and parabiosis-mediated exposure of young and old blood on microglia subpopulations across four different brain regions including cerebellum, cortex, hippocampus, and striatum. We revealed region-specific differences in microglia subpopulation composition and age-related changes, with cerebellum and striatum displaying the most distinctive profiles and dynamic shifts compared to other brain regions. We consistently observed cerebellum as the most responsive, while striatum appeared distinctive by its minimal responsiveness to these interventions. Our findings highlighted the role of microglia in brain regional vulnerability and provided a foundation for microglia-targeted treatment for modulating brain aging.
Highlights: Defined the composition of different microglial populations reproducible in aging and parabiosis, benchmarking a reference for the field.Uncovered an under-appreciated core activation gene signature of microglia shared in all reactive states and regions during normal aging and old blood-induced aging.Identified region-specific gene expression changes and associated biological processes in microglia during aging and parabiosisDiscovered microglial regional selectivity in response to aging and parabiosis, showing cerebellum as the most sensitive region and the striatum as the least affected.

DOI: https://doi.org/10.1101/2025.10.29.685417
bioRxiv. 2025 Oct 20. pii: 2025.10.19.683343. [Epub ahead of print]

Transcriptomic profiling of the middle temporal gyrus reveals differential glial/neuronal dysregulation across Alzheimer's disease and aging.

I S Piras, A Bonfitto, S Song, A Aldabergenova, J Sloan, A Trejo, J C Troncoso, C Geula, E J Rogalski, C H Kawas, M Corrada, T G Beach, G E Serrano, P F Worley, C A Barnes, M J Huentelman.

Alzheimer's disease (AD), the most common cause of dementia, is characterized by amyloid-β plaques, neurofibrillary tangles, and widespread neuronal dysfunction. Aging, the strongest risk factor for AD, is also associated with some overlapping processes, such as neuronal cell transcriptional downregulation and glial cell activation. The middle temporal gyrus (MTG) is a brain region that supports semantic processing and default-mode connectivity and shows early vulnerability in both aging and AD. Here we profile bulk RNA-seq from 606 postmortem MTG samples with the goal of understanding the transcriptional changes associated with AD and aging. In 217 clinical and neuropathologically confirmed AD versus 290 no-dementia controls donors, we identify 613 differentially expressed genes (390 up, 223 down; |log2 fold change| ≥ 0.5; BH P < 0.05), with NPNT and ADAMTS2 among the top upregulated signals. Cell set enrichment indicates reduced excitatory neuronal signatures together with increased microglial, astrocytic, endothelial, and pericyte programs. Gene-set analyses reveal strong activation of angiogenesis, extracellular-matrix organization, wound response, adaptive immunity, and coordinated suppression of neuronal and mitochondrial processes, including synaptic signaling and respiratory-chain complexes. Multiscale coexpression mapping resolves three disease clusters: a neuron-mitochondrial module suppressed in AD (M5; hub PJA2; key driver GABRB3), a microglial immune module upregulated in AD (M6; hub C1QC; key driver FCER1G), and an increased astrocyte-vascular extracellular-matrix module in AD (M8; hub ESAM; key driver TAGLN). Across 324 non-AD controls aged 24-108 years, aging is associated with declines in gene expression associated with translation, proteostasis, and mitochondrial function and increases in those linked to oligodendrocyte and myelination programs (for example M4; hub CNTN2; key driver MOBP); in a 65+ subset, neuronal and protein-folding modules show the strongest decrements with reduced glial gene expression upregulatio. Our results indicate that late-life aging involves increased glial responses and neuronal/proteostasis suppression, whereas AD is also associated with immune- vascular-ECM activation and suppression of neuronal programs.

DOI: https://doi.org/10.1101/2025.10.19.683343
bioRxiv. 2025 Nov 07. pii: 2025.11.05.686857. [Epub ahead of print]

The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies.

Carlos M Soto-Faguás, Abigail O'Niel, Paul A Mueller, Paula Sanchez-Molina, Randy L Woltjer, Jacob Raber, Vivek K Unni.

Apolipoprotein E ( APOE ) genotype is well known to influence both amyloid-β (Aβ) and tau pathologies and risk for Alzheimer's disease (AD), but it also affects α-synuclein (α-syn) levels, Lewy pathology and risk of dementia in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The APOE-R136S (Christchurch, CC) point mutation has been shown to protect against AD pathology and dementia, however, the molecular mechanisms underlying this protection and its effects on α-syn pathology are not well understood. Using CRISPR/Cas9 technology, we created a CC arginine-to-serine point mutation at the conserved location in mouse APOE (R128S) to understand its effects on Aβ, tau and α-syn pathologies. We crossed these APOE CC mice to 5xFAD, PS19 and A53T-αSyn-GFP (A53T) mice. Using these various double mutant mice, we tested the effect of mouse APOE CC on different proteinopathies, including Aβ, tau, Aβ-induced tau after paired helical filament (PHF)-tau intracortical injections, and α-syn after preformed fibril (PFF) intracortical and intramuscular injections. We used immunohistochemical, biochemical and behavioral measures to test for protective effects of APOE CC on these different proteinopathies. Heterozygous (Het) and homozygous (Hom) APOE CC mice showed increased plasma cholesterol and triglyceride levels, as seen in humans, but no differences in body or brain weight, or life expectancy. APOE CC decreased Aβ-induced tau pathologies in PHF-tau injected 5xFAD;Hom mice but did not change Aβ-plaque pathology in 5xFAD mice or tau pathology in PS19 mice. Although Aβ levels, tau levels and mouse sex correlated strongly with the behavioral performance, we only detected subtle effects of APOE CC on anxiety-like behaviors in crosses with 5xFAD, PS19 and PHF-tau injected 5xFAD mice. Interestingly, Het and Hom APOE CC mice both showed reduced formation and spread of Lewy pathology in brain after intracortical α-syn PFF injection and reduced formation in spinal cord after α-syn PFF injection into the hindlimb gastrocnemius muscle in A53T mice. Our study emphasizes the protective effects of the APOE CC variant against different proteinopathies important for dementia and movement disorders, including Aβ plaque, tau and α-syn, and suggests that targeting APOE CC could provide new therapeutic strategies for AD, DLB and PD.

DOI: https://doi.org/10.1101/2025.11.05.686857
bioRxiv. 2025 Oct 16. pii: 2025.10.16.682921. [Epub ahead of print]

Mapping cross-domain drivers of Alzheimer's disease risk through integrated network analysis.

Emory-Sage-SGC-JAX TREAT-AD Center

Introduction: Alzheimer's Disease (AD) is a complex neurodegenerative disorder with numerous known risk factors. Identification of which genetic factors are causal drivers is difficult due to the long disease prodrome in an inaccessible organ. The application of integrative, systems-level approaches are crucial for addressing this complexity.
Methods: Sixteen biological domain specific interaction networks were derived from the top AD risk- enriched proteins within each domain. Weighted key driver analysis identified influential hub nodes within each network.
Results: Distinct processes and drivers were identified within each domain's network. Domains including Structural Stabilization, Endolysosome, and Lipid Metabolism were especially influential. Integrating key drivers across domains identified consistent drivers such as CTNNB1, ACSL1, and ALDH3A2, suggesting fundamental roles contributing to AD risk.
Discussion: This highly integrative network-based approach identified context-dependent drivers and enabled the inference of interactions between domains. The identified drivers suggest potential targets for future therapeutic development.

DOI: https://doi.org/10.1101/2025.10.16.682921
bioRxiv. 2025 Nov 11. pii: 2025.11.11.687887. [Epub ahead of print]

APOE4-Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation a preclinical Alzheimer's disease model.

Jia Shin, Erica Brady, Chun Chen, Kelli Lauderdale, Ayushi Agrawal, Yutong Zhang, Xueqiao Jiang, Pranav Nambiar, Jessica Herbert, Dakota D Mallen, Katie K Ly, Patrick S Honma, Zhongyi Guo, Cathrine Sant, Reuben Thomas, Stephanie R Miller, Inma Cobos, Jorge J Palop.

Amyloid-β (Aβ) and APOE4 represent two of the strongest pathological and genetic risk factors for Alzheimer's disease (AD), but how these co-pathogens interact during preclinical stages remains undefined. We addressed this question by developing a humanized knock-in model expressing physiological, endogenously regulated human Aβ and APOE4. Aged App NLF :APOE4 mice displayed incipient amyloidosis with subtle memory-related changes, consistent with preclinical AD. We found largely distinct, non-overlapping APOE4- and Aβ-driven functional synaptic, sleep, and behavioral alterations. However, at the transcriptomic level, APOE4xAβ had a pronounced detrimental interaction in neuronal populations, whereas glial populations were primarily affected by either genotype. We found APOE4xAβ molecular interactions in neuronal populations, including excitatory and inhibitory cells, converged on a core lysosomal-ER proteostasis axis. We propose that APOE4xAβ interaction produces an early neuronal pathogenic signature, involving the lysosomal-ER proteostasis axis, preceding functional decline and driving disease progression. APOE4xAβ-KI models provide a physiologically relevant platform to study early pathogenesis.
Highlights: Early synergistic APOE4xAβ interaction emerges predominantly at the transcriptomic level in neurons, but not in glial cells.APOE4 and Aβ drive largely non-overlapping physiological changes in preclinical stages of disease, but converge at the level of network hyperexcitability.APOE4xAβ neuronal synergy converges on a conserved lysosomal-ER proteostasis axis.Humanized APOE4xAβ KI mice provide a physiologically relevant model to dissect early AD pathogenesis in preclinical stages.

DOI: https://doi.org/10.1101/2025.11.11.687887
Nat Commun. 2025 Nov 24. 16(1): 10354

Transient overexpression of hPKM2 in porcine cardiomyocytes prevents heart failure after myocardial infarction.

Jiacheng Sun, Yalin Wu, Matthew Adjmi, Rachel C Matthews, Ann Anu Kurian, Magdalena M Żak, Jimeen Yoo, Gayatri Mainkar, Hannah Lawless, Yu-An Lu, Patrick Soon-Shiong, Gregory P Walcott, Hesham A Sadek, Jianyi Zhang, Lior Zangi.

The adult mammalian heart lacks the ability to regenerate after injury, contributing to heart failure. No current treatment reactivates heart muscle cell division to prevent this decline. We used a targeted, non-viral modified mRNA system to transiently boost expression of a regenerative enzyme, pyruvate kinase muscle isozyme M2, in heart muscle cells of juvenile and adult pig models after ischemic injury. In juvenile pigs treated one-week post-injury, we observed increased markers of cell division, secretion of protective factors, improved heart function, and reduced scarring two months later. In adult pigs treated immediately after injury, we saw improved heart contractility and less fibrosis one month later. These results show that targeted pyruvate kinase muscle isozyme M2 modified mRNA delivery can stimulate muscle regeneration and functional recovery in both young and adult pig hearts. This approach offers a promising strategy for repairing ischemic injury and preventing heart failure in humans.

DOI: https://doi.org/10.1038/s41467-025-65344-4
Sci Adv. 2025 Nov 28. 11(48): eadz1243

Brain-derived extracellular vesicles circUsp32 polarized macrophages causing acute kidney injury after traumatic brain injury.

Jiayuanyuan Fu, Jingheng Wu, Mengran Du, Xu Wang, Qi Shi, Yehong Fang, Yu Lan, Qiaoli Wu, Guobin Zhang, Lixia Xu, Hua Yan.

Brain-kidney cross-talk following traumatic brain injury (TBI) can induce acute kidney injury (AKI), but mechanisms remain unclear. Extracellular vesicles derived from injured brain tissue (TBI-EVs) may mediate brain-kidney interactions. In vivo experiments demonstrated that TBI-EVs causes AKI by promoting pro-inflammatory macrophage polarization. TBI-EVs markedly increased AKI markers and proportion of pro-inflammatory-polarized macrophages. Mechanistically, transcriptomics of TBI-EVs revealed high circUsp32 expression. Subsequent in vitro assays showed that circUsp32 competitively binds to the SH2 domain of suppressor of cytokine signaling 1 (Socs1), affecting interferon regulator factor 7 (IRF7) ubiquitination and promoting pro-inflammatory polarization. CircUsp32 knockdown reduced pro-inflammatory polarization and alleviated AKI in TBI mice. In addition, circUsp32 is homologous to hsa_circ_0044940, which may serve as a predicted biomarker of AKI after TBI. Notably, AKI following TBI may contribute to neuroinflammation via uremic toxins. Collectively, these findings suggest that circUsp32 mediates macrophage polarization through the Socs1/IRF7 axis and could be a potential biomarker for AKI following TBI.

DOI: https://doi.org/10.1126/sciadv.adz1243
J Neurochem. 2025 Nov;169(11): e70307

Development and Validation of an ICP-MS/MS Method for the Multielemental Analysis of Cerebrospinal Fluid, Examination of Alzheimer's Disease Samples.

Rebeca Pérez-Ramírez, Inmaculada Cuchillo-Ibáñez, Raquel Sánchez-Romero, Ana Beltrán-Sanahuja, Sergio Escamilla, Ricardo Molina-Gasset, Henrik Zetterberg, Kaj Blennow, Javier Sáez-Valero, José-Luis Todolí-Torró.

  Multielemental analysis of cerebrospinal fluid (CSF) yields critical insights into the pathophysiology of neurological disorders and holds potential as a diagnostic and predictive tool for Alzheimer's disease (AD). The present work presents the development and validation of an inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) based method for multielemental determination in CSF, including metals and metalloids as analytes. As a proof of concept, the importance of the CSF element determination was evaluated in a cohort of patients with AD (n = 20) and non-AD controls (n = 19) who displayed typical levels of core CSF biomarkers (Aβ42, P-tau, and total-tau). Discrete sample introduction ICP-MS/MS procedure was effective for accurate and precise CSF analysis. The methodology provided better sensitivities and limits of detection than a conventional one based on sample dilution and analysis in continuous sample introduction mode, while only requiring a 20 μL CSF sample volume. A total of 24 elements were encountered and quantified in CSF, with reduced levels of Mn, Cr, Se, Fe, and Zn in the CSF from AD patients and increased levels of Ag and Bi, compared with non-AD patients. Particularly, Mn fully discriminated AD from non-AD subjects, with binary regression analysis indicating that Mn was the most effective element to distinguish between AD and non-AD groups. Furthermore, distinctive correlation profiles were found between AD and non-AD controls for elements with AD core biomarkers and the alternative amyloidogenic sAPPβ fragment. Quantitative determination of metals, metalloids and non-metals displays differences associated with pathological status, serving as additional biomarkers for neurological diseases.

Keywords:  Alzheimer's disease; CSF; ICP‐MS/MS; Mn; biomarker; chemical elements

DOI:  https://doi.org/10.1111/jnc.70307
Metab Brain Dis. 2025 Nov 25. 40(8): 326

"Rewiring brain immunity: targeting microglial metabolism for neuroprotection in neurodegenerative disorders".

Mustafa M Shokr.

  Neuroinflammation, a pervasive hallmark in many neurological and neuropsychiatric diseases, is largely dictated by the functional phenotypic dynamics of microglia, the immune system of the brain. Recent data illustrate that these phenotypic changes, from neuroprotective scavenging to neurotoxic pro-inflammatory effects, are intrinsically regulated by microglial metabolic repolarization. This review synthesizes understanding of discrete microglial metabolic phenotypes like the glycolytic reliance of pro-inflammatory (M1-like) microglia and the oxidative phosphorylation/fatty acid oxidation bias of anti-inflammatory/resolving (M2-like) microglia. We discuss how central metabolic sensors like AMPK, mTOR, and HIF-1α oversee these metabolic shifts in response to disease-targeted pathologies in Alzheimer's, Parkinson's, Multiple Sclerosis, ischemic stroke, and traumatic brain injury. Moreover, we review innovative therapeutic strategies directed toward microglial metabolism, involving pharmacological modulators (e.g., metformin, rapamycin, and ketone bodies), nutritional interventions (e.g., ketogenic diets), and modulation of gut microbiota. By tightly specific re-tuning of microglial cells' bioenergetics, these approaches enable unprecedented opportunities to counteract neuroinflammation, enhance pathological clearance, and induce neuroprotection, paving the way for a new generation of disease-modifying therapies of neurodegenerative disorders.

Keywords:  Metabolic reprogramming; Microglial metabolism; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1007/s11011-025-01739-y
Mol Neurobiol. 2025 Nov 24. 63(1): 160

White Blood Cells in Neurodegenerative Diseases in the Context of Neuroinflammation.

Agnieszka Wełnicka-Wesołowska, Monika Gołąb-Janowska.

  Neurodegenerative diseases are a multifactorial problem for modern neurology, due to their unknown etiology, difficult diagnostics, and, consequently, the lack of causal methods of treatment. Rising life expectancy exacerbates the problem by increasing the number of patients, as most of them fall ill in older age. Recent research shows that inflammation, both peripheral and neuroinflammation, may take part in the pathogenetic pathways of disease development. Some studies suggest that the initiation of the process occurs outside of the nervous system and is causally related to the immune system. This review focuses on the role of basic peripheral immune cells, including lymphocytes and neutrophils, in the course of selected central nervous system pathologies and their potential use as a biomarker. Both types of leukocytes not only change their quantity, but, more importantly, their function. Furthermore, they interact with microglial cells that constantly surveil the central nervous system and respond to pathological factors. Their joint action, however, can be either neuroprotective or neurotoxic. This review highlights that the development of neurodegeneration is associated with a dysregulation of the balance between immune cell phenotypes and their interactions. The disturbed immune response does not allow for the organism to correctly control the disease.

Keywords:  Lymphocytes; Neurodegenerative diseases; Neuroinflammation; Neutrophils; White blood cells

DOI:  https://doi.org/10.1007/s12035-025-05476-2
Alzheimers Res Ther. 2025 Nov 26. 17(1): 252

The relationship between amyloid-β peptide spectrum and the spastic paraparesis phenotype in autosomal dominant Alzheimer's disease.

Katarzyna Marta Zoltowska, Julia Bandera, Mohamed Belal Hamed, Thomas Enzlein, Carsten Hopf, Natalie S Ryan, Lucía Chávez-Gutiérrez.

   BACKGROUND: More than 300 mutations in presenilin 1 (PSEN1) lead to autosomal dominant Alzheimer's disease (ADAD). PSEN1, as the catalytic subunit of γ-secretase, generates amyloid-β (Aβ) peptides through a sequential proteolysis of the amyloid precursor protein (APP). While ADAD typically presents with progressive cognitive decline, ~ 25% of PSEN1 mutation carriers develop spastic paraparesis (SP), a debilitating motor condition. The molecular basis of this phenotypic heterogeneity remains unknown. This study examines Aβ profiles generated by PSEN1 variants associated with different clinical presentations with the aim of exploring potential associations between different Aβ profiles and clinical heterogeneity.
METHODS: We analysed reported Aβ peptide profiles generated in vitro by 160 PSEN1 variants, categorized by their associated AD or AD + SP phenotype. We employed an integrated analytical approach combining univariate comparisons of Aβ profiles with machine learning classification.
RESULTS: AD + SP-linked mutations showed significantly higher Aβ43 levels and more severe impairments in γ-secretase processivity compared to pure dementia associated variants. Machine learning consistently identified Aβ43 as the most important feature allowing for the phenotypic classification. Unlike processivity impairments, total Aβ production was comparable between groups, suggesting specific rather than global alterations in γ-secretase function.
CONCLUSIONS: Our analysis reveals a robust association between elevated Aβ43 levels and SP development in PSEN1 mutation carriers. While this correlation does not establish causation, the distinct impact of SP-associated mutations on γ-secretase function, resulting in elevated Aβ43 production, suggests that mutation-specific mechanisms may underlie clinical heterogeneity in ADAD, with potential implications for biomarker and translational research.

Keywords:  Amyloid beta; Autosomal dominant Alzheimer’s disease; Motor impairments; Presenilin 1; Spastic paraparesis; Spasticity

DOI:  https://doi.org/10.1186/s13195-025-01896-3
Mol Neurobiol. 2025 Nov 27. 63(1): 189

Cellular and Extracellular MicroRNA Dysregulation in LRRK2-Linked Parkinson's Disease.

Felix Knab, Jun-Hoe Lee, Raja Nirujogi, Kevin Menden, Luca Braunger, Lambrianna Logarnudi, Benjamin Riebenbauer, Fatma Busra Isik, Anto Praveen Rajkumar, Stefan Czemmel, Julia Fitzgerald, Thomas Gasser, Christian Johannes Gloeckner.

  Cell-free microRNAs in body fluids have emerged as promising biomarker candidates in neurodegenerative diseases. While several studies have identified dysregulated miRNAs in sporadic Parkinson's disease, it remains unclear whether distinguishable alterations of cell-free miRNAs occur in genetic forms of the disease, such as those associated with the LRRK2 G2019S mutation. In this proof-of-concept study, we used a human induced pluripotent stem cell-derived dopaminergic neuron model to investigate whether the LRRK2 G2019S mutation induces detectable changes in the intra- and extracellular miRNAome, and whether miRNA signatures identified in vitro can be validated in patient-derived cerebrospinal fluid. We differentiated dopaminergic neurons from induced pluripotent stem cells carrying the LRRK2 G2019S mutation and an isogenic gene-corrected control. Extracellular vesicles were isolated from the culture medium and used as a source of cell-free miRNA. Next, small RNA libraries were generated and analyzed. Differentially expressed microRNAs were validated in an independent batch using RT-qPCR. We further quantified candidate microRNAs in cerebrospinal fluid samples from five LRRK2 G2019S patients and matching healthy controls. The patient cohort included the fibroblast donor from whom the stem cells were originally derived. We successfully isolated extracellular vesicles from induced pluripotent stem cell-derived human dopaminergic neurons. We identified a distinct set of differentially expressed miRNAs in cellular and cell-free RNA, among which let-7g-5p and miR-21-5p were consistently upregulated and validated across independent replicates. These alterations were reflected in the cerebrospinal fluid of the original donor and partially reproduced in additional LRRK2 patients, supporting the concept of patient-specific signatures. A strong correlation between intra- and extracellular miRNA expression was observed. Our findings demonstrate that induced pluripotent stem cell-derived dopaminergic neurons can serve as a model to identify individualized, cell-free microRNA signatures associated with the LRRK2 G2019S mutation. The dysregulated miRNAs detected in vitro were mirrored in patient cerebrospinal fluid, supporting their potential as accessible molecular readouts. These results lay the groundwork for personalized biomarker strategies in genetic forms of Parkinson's disease and warrant further validation in larger patient cohorts.

Keywords:  Biomarker; IPSCs; LRRK2; Micro-RNA; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-025-05379-2
FASEB J. 2025 Dec 15. 39(23): e71271

Altered Lipid Metabolism in the Vaginal Wall of Women With Pelvic Organ Prolapse: A Targeted Lipidomics Study.

Shufei Zhang, Hanyue Li, Xiaoyu Tian, Hongyang Xue, Yong He, Nuo Jiang, Li Hong.

  Pelvic organ prolapse (POP) severely impacts quality of life, but its association with lipid metabolism remains unclear. This study explored lipidomic alterations in vaginal anterior wall tissues of POP patients. We performed UHPLC-MS/MS-based targeted lipidomics on vaginal anterior wall tissues from 8 POP patients and 8 matched controls. Multivariate analyses (PCA, PLS-DA, OPLS-DA) identified significantly altered lipids, and KEGG pathway analysis determined related metabolic pathways. Among 1010 identified lipids, POP tissues exhibited significant lipid remodeling: phosphatidic acid (PA) increased from 0.048% to 0.226%, triglycerides (TG) decreased from 94.901% to 83.927%. Forty- four lipids were significantly altered (VIP > 1, p < 0.05), with KEGG analysis highlighting enrichment in glycerophospholipid metabolism. Reprogramming of lipid chain length and saturation further confirmed metabolic dysregulation. POP may be associated with disrupted lipid metabolism, characterized by elevated PA/PE/PC and reduced TG, potentially impairing membrane stability, mitochondrial function, and energy homeostasis. These findings reveal novel molecular mechanisms in POP and suggest lipid metabolism as a therapeutic target.

Keywords:  UHPLC–MS/MS; glycerophospholipid; lipid metabolism; pelvic organ prolapse; targeted lipidomics

DOI:  https://doi.org/10.1096/fj.202502840R
Cell Rep. 2025 Nov 26. pii: S2211-1247(25)01408-1. [Epub ahead of print]44(12): 116636

Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination.

Zhijie Zhou, Zhangyuzi Deng, Yingying Huang, Jian Chen, Jing Yang, Ying Cao.

  Neuromyelitis optica spectrum disorder, often linked to autoimmune antibodies against aquaporin-4 (AQP4), is a demyelinating disease exhibiting a profound sex bias in female patients. However, the pathophysiological mechanism underlying this clinical manifestation remains to be better understood. In this study, we observe a higher extent of neuroinflammation and demyelination in female mice than in males with the AQP4 antibody-induced disease model. Of importance is that sex hormone depletion in ovariectomized female mice is sufficient to mitigate the disease severity, while estradiol replacement in castrated male mice exacerbates these neuropathological features. We then demonstrate that microglia predominantly express estrogen receptor 1 (Esr1) and that specific deletion of Esr1 inhibits microglia-mediated neuroinflammation and reduces demyelination. Moreover, the administration of fulvestrant, a clinically approved estrogen receptor antagonist, can effectively ameliorate the mouse disease model. These results have elucidated a critical, proinflammatory role of the microglial Esr1 signal in AQP4 antibody-induced neuroinflammation and demyelination with clinical implications.

Keywords:  CP: immunology; CP: neuroscience:; estrogen receptor 1; fulvestrant; microglia; neuromyelitis optica spectrum disorder; sexual dimorphism

DOI:  https://doi.org/10.1016/j.celrep.2025.116636
Commun Biol. 2025 Nov 24. 8(1): 1660

Alzheimer's Tau seeds-induced pathology enhances hippocampal extracellular diffusion.

Juan Estaún-Panzano, Anna Lovisotto, Claire Mazzocco, Carolina Piva, Morgane Darricau, Ivo Calaresu, Quentin Gresil, Vincent Planche, Benjamin Dehay, Laurent Groc, Laurent Cognet, Erwan Bezard.

The extracellular space (ECS) is a complex, dynamic network occupying about 20% of the brain, filled with a cerebrospinal fluid-like solution rich in extracellular matrix (ECM) molecules. ECS properties regulate molecular diffusion, potentially influencing disease-associated protein spread in neurodegenerative diseases. However, its role in tau propagation remains unexplored. Using wild-type mice injected with tau seeds purified from Alzheimer's disease brain, we applied quantum dot single-particle tracking in live tissue to examine how tau pathology and inflammation influence extracellular diffusion. We observed increased diffusion associated with tau pathology in specific hippocampal regions. Additionally, diffusion profiles differed between cell-dense and cell-sparse areas. Astrocytes showed abnormal internalisation of proteoglycans, and matrix structural components were dysregulated, suggesting a link between altered ECM dynamics and enhanced diffusion. Increased diffusion and altered ECM dynamics might facilitate the spread of tau pathology.

DOI: https://doi.org/10.1038/s42003-025-09054-z
Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01391-7. [Epub ahead of print]243 318-337

NRF2 activation by CDDO-Im regulates inflammatory and autophagy pathways in human microglial cells.

Ching-Tung Chu, Akira Uruno, Takafumi Suzuki, Keiko Taguchi, Liam Baird, Fumiki Katsuoka, Masayuki Yamamoto.

  Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-γ or Aβ. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative direct NRF2 target genes involved in inflammation (e.g., IL6, CDK6) and another five related to autophagy (e.g., TFE3, SQSTM1). Importantly, we also found that CDDO-Im treatment enhances autophagy as evidenced by an increased LC3-II/LC3-I ratio. Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Together, our findings reveal new direct NRF2 target genes, highlight the dual role of NRF2 in suppressing inflammation and enhancing autophagy, and thus provide novel insights for therapeutic interventions in AD.

Keywords:  Alzheimer's disease (AD); Amyloid beta (Aβ); Interferon-gamma (IFN-γ); Microglia; NRF2 activation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.046
bioRxiv. 2025 Nov 05. pii: 2025.11.03.685977. [Epub ahead of print]

Ablation of microglial estrogen receptor alpha predisposes to diet-induced obesity in male mice.

Inmaculada Velasco, Jeremy M Frey, Vladislav Baglaev, Tristan Jafari, Thomas Huang, Sophia Schwie, Olivia D Santiago, Rachael D Fasnacht, Joshua P Thaler, Mauricio D Dorfman.

Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. In male but not female mice, inflammatory activation of microglia, the resident macrophages of the brain, has been implicated in the pathogenesis of diet-induced obesity (DIO), raising the possibility that differences in microglial estrogen signaling may account for the sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ERα (MG-ERαKO). Male MG-ERαKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry analysis revealed that reduced energy expenditure was the main driver of the obese phenotype. In contrast, female MG-ERαKO mice fed HFD developed mild insulin resistance with no change in body weight gain compared to controls. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERαKO mice had increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERαKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERαKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.

DOI: https://doi.org/10.1101/2025.11.03.685977
bioRxiv. 2025 Oct 29. pii: 2025.10.29.685332. [Epub ahead of print]

Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling.

Drew Adler, Alejandro Martín-Ávila, Evan Cheng, Mauricio M Oliveira, Muxian Zhang, Harrison T Evans, Deliang Yuan, Richard Sam, Nicole D Zhang, Maria Clara Selles, Olivia Mosto, Wendy J Liu, Amy X Guo, Shane A Liddelow, Robert C Froemke, Moses V Chao, Wen-Biao Gan, Eric Klann.

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here we demonstrate that microglia, resident macrophages of the brain, coordinate metabolic coupling between endothelial cells, astrocytes, and neurons to fuel protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, increasing glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit required for on-demand protein synthesis in mouse motor cortex.

DOI: https://doi.org/10.1101/2025.10.29.685332
Nat Commun. 2025 Nov 26.

Spatiotemporal patterns differentiate hippocampal sharp-wave ripples from interictal epileptiform discharges in mice and humans.

Anna Maslarova, Jiyun N Shin, Andrea Navas-Olive, Mihály Vöröslakos, Hajo Hamer, Arnd Doerfler, Simon Henin, György Buzsáki, Anli Liu.

Hippocampal sharp-wave ripples (SPW-Rs) are high-frequency oscillations critical for memory consolidation. Despite extensive characterization in rodents, their detection in humans is limited by coarse spatial sampling, interictal epileptiform discharges (IEDs), and a lack of consensus on human ripple localization and morphology. Here, we demonstrate that mouse and human hippocampal ripples share spatial, spectral and temporal features, which are clearly distinct from IEDs. In recordings from male APP/PS1 mice, SPW-Rs were distinguishable from IEDs by multiple criteria. Hippocampal ripples recorded during NREM sleep in female and male surgical epilepsy patients exhibited similar narrowband frequency peaks and multiple ripple cycles in the CA1 and subiculum regions. Conversely, IEDs showed a broad spatial extent and wide-band frequency power. We developed a semi-automated, ripple curation toolbox (ripmap) to separate event waveforms by low-dimensional embedding to reduce false-positive rate in selected ripple channels. Our approach improves ripple detection and provides a firm foundation for future human memory research.

DOI: https://doi.org/10.1038/s41467-025-66562-6
Mol Neurobiol. 2025 Nov 28. 63(1): 195

Every-Other-Day Feeding Prevents the Loss of Parvalbumin-Expressing Neurons in the Cerebral Cortex of Female 5xFAD Mice.

Jelena Ciric, Milka Perovic, Nikola Milovanovic, Suryanarayana Polaka, Irena Jovanovic Macura, Natasa Nestorovic, Vesna Tesic.

  The present study demonstrates the effects of an every-other-day (EOD) feeding regimen on parvalbumin (PV)-expressing interneurons in the cortex of 5xFAD mice, a well-established animal model of Alzheimer's disease (AD). Female 5xFAD mice and their non-transgenic littermates were maintained on either an ad libitum (AL) or EOD feeding regimen throughout the presymptomatic phase of the pathology, with comprehensive immunohistochemical and Western blot analyses performed in 6-month-old animals. In AL-fed 5xFAD mice, significant reductions in PV-expressing interneurons were observed in the retrosplenial granular, parietal, and somatosensory cortices compared to non-transgenic controls, supporting their established vulnerability in AD pathology. This neuronal loss was accompanied by a decline in the levels of brain-derived neurotrophic factor (BDNF), a key neurotrophin essential for cell survival and synaptic plasticity. Remarkably, four months of EOD feeding prevented the Aβ-induced loss of PV interneurons and increased the total protein levels of the BDNF receptor TrkB, suggesting enhanced neurotrophic signaling. However, the benefits of EOD feeding were not uniform across all molecular markers, with EOD-fed 5xFAD mice retaining deficits in phosphorylated CaMKII and CREB-binding protein (CBP) and biochemical analysis of plasma indicating metabolic stress-related effects. Together, these results align with the GABAergic hypofunction hypothesis in AD, underscoring the importance of PV interneuron plasticity in neurodegeneration and cognitive decline. They also suggest that dietary strategies like EOD feeding may offer partial neuroprotective effects during early AD progression, however, complex stress-related impacts of EOD in the modulation of PV neuron function remain to be elucidated. Future studies are also warranted to more carefully explore the long-term translational potential of dietary interventions and the interplay between metabolic stress and amyloid pathology, in order to identify novel therapeutic targets across distinct neuronal populations.

Keywords:  Alzheimer’s disease; BDNF; CBP; EOD feeding; Food restriction; Parvalbumin

DOI:  https://doi.org/10.1007/s12035-025-05355-w
STAR Protoc. 2025 Nov 24. pii: S2666-1667(25)00625-2. [Epub ahead of print]6(4): 104219

Protocol for in vitro phagocytosis assay for primary mouse microglia and human embryonic stem cell-derived microglia.

Beika Zhu, Alicia L Thurber, Xianhua Piao.

  Microglia, the resident immune cells of the brain, maintain brain health by clearing detrimental debris, including amyloid-β (Aβ). Here, we present a protocol for assessing Aβ uptake by primary mouse microglia and human embryonic stem cell-derived microglia using an in vitro phagocytosis assay. We describe procedures for pHrodo-labeled oligomeric Aβ treatment and real-time signal detection using the Incucyte SX5 system. We also detail steps for microglia culture, Aβ labeling, and quantification of phagocytosis over time. For complete details on the use and execution of this protocol, please refer to Zhu et al.1.

Keywords:  Cell-based Assays; Immunology; Model Organisms; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2025.104219
Nat Commun. 2025 Nov 26. 16(1): 10514

Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer's disease.

Lu Wang, Xiao-Yong Xie, Qiu-Ling Pan, Jiawei Zhang, Gui-Feng Zhou, Qi-Lei Zhang, Xiao-Xin Yan, Yu Xiang, Chen-Lu Li, Yi He, Xiao-Jiao Xiang, Xiao-Juan Deng, Yan-Jiang Wang, Ji-Ying Zhou, Shenyou Nie, Guo-Jun Chen.

Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD.

DOI: https://doi.org/10.1038/s41467-025-65547-9