bims-micgli 2025-08-31 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–08–31
seventeen papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.
Repopulation of microglia and its implications for CNS disorders: Insights from the single-cell era.
Cyclooxygenase-1 deletion in 5 × FAD mice protects against microglia-induced neuroinflammation and mitigates cognitive impairment.
Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health.
TREM2 and Pain Development: An Old Molecule, a New Target.
The Multifaceted Role of Extracellular Vesicles in Alzheimer's Disease.
Connexin 43 Role in Mitochondrial Transfer and Homeostasis in the Central Nervous System.
ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.
Modulation of Amyloid-β Aggregation by Surface Proteins from Pathogens Associated with Alzheimer's Disease.
Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells.
Neutrophils-astrocyte interactions in central nervous system inflammation.
ApoE-calypse tau: ApoE-tau synergy in Alzheimer's disease.
RABGAP1 is a sensor that facilitates the sorting and processing of amyloid precursor protein.
Extracellular tau clearance is governed by its aggregation state and independent of microglial activation by LPS and IFN-γ.
Understanding monocyte-driven neuroinflammation in Alzheimer's disease using human cortical organoid microphysiological systems.
Retinal tau phosphorylation in Alzheimer's disease: A mass spectrometry study.
IGFBP2-Ceramides Pathway Mediates Divergent Myelin Breakdown in the PNS and CNS Following Injury.

Alzheimers Dement. 2025 Aug;21(8): e70580

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.

Emma P Danhash, Anthony C Verbeck, Daniel Western, Andrea S Díaz-Pacheco, Grant Galasso, Shih-Feng You, Guangming Huang, Emma Starr, Nadia Miller, Collin J Nadarajah, Savannah Tiemann Powles, Erik S Musiek, Jasmin Herz, Abhirami K Iyer, John Cirrito, Carlos Cruchaga, Celeste M Karch.

   INTRODUCTION: Genome-wide association studies have identified MS4A4A, a microglia-enriched gene, as a modulator of Alzheimer's disease (AD) risk. Common variants in MS4A4A affect AD susceptibility, gene expression, triggering receptor expressed on myeloid cells 2 (TREM2) signaling, and microglial transcriptional states, but the gene's functional role remains unclear.
METHODS: Using a novel model, we investigated the impact of Ms4a4a loss in the 5xFAD mouse model of amyloid beta (Aβ) accumulation.
RESULTS: Ms4a4a deficiency reduced steady-state Aβ levels and shortened its half-life in brain interstitial fluid. Aged 5xFAD mice lacking Ms4a4a exhibited more compact plaques and lower overall plaque burden. Microglia deficient in Ms4a4a showed a pro-inflammatory profile and elevated matrix metalloproteinase 9 (MMP-9) production, which may facilitate Aβ degradation. Notably, human carriers of the AD-resilient variant rs1582763 near MS4A4A also displayed increased cerebrospinal fluid MMP-9 levels.
DISCUSSION: Together, we show that Ms4a4a loss enhances Aβ clearance and reduces pathology, suggesting a protective mechanism that may inform microglia-targeted AD therapies.
HIGHLIGHTS: We examined the impact of Ms4a4a loss on amyloid beta (Aβ) pathology using a mouse model of Aβ accumulation (5xFAD). Ms4a4a loss reduces overall plaque burden and increases plaque compaction. Microglia lacking Ms4a4a are more pro-inflammatory and produce more matrix metalloproteinase 9 (MMP-9). Alzheimer's disease (AD) resilience variant carriers, MS4A4A rs1582763, exhibit significantly elevated levels of cerebrospinal fluid MMP-9. Our findings suggest that reduction of MS4A4A may be a therapeutic approach for AD.

Keywords:  Alzheimer's disease; MS4A4A; amyloid beta clearance; animal model; microglia; resilience

DOI:  https://doi.org/10.1002/alz.70580
Neurobiol Dis. 2025 Aug 25. pii: S0969-9961(25)00282-7. [Epub ahead of print]215 107066

Repopulation of microglia and its implications for CNS disorders: Insights from the single-cell era.

Cong Chen, Guanjia Qiao, Dantong Tang, Fengling Xu, Jiawen Dong, Jinpan Zhang, Boru Jin.

  Microglia, as resident macrophages in the central nervous system (CNS), have been the focus of the scientific community. The pace of exploration in the origin and development of microglia, though tortuous, never stops. Since colony-stimulating factor receptor 1 (CSF1R) inhibitors can achieve effective depletion of microglia and the repopulated microglia can be comparable to the controls, the therapeutic potential of this repopulation has prompted increasing attention and investigation. Meanwhile, single-cell sequencing technology (scRNA-seq) revealed cell fate determination and cell heterogeneity of microglia during development, homeostasis, and pathological states, identifying various functional subpopulations, including disease-associated microglia (DAM), neurodegenerative microglia (MGnD), and others. Thus, novel therapeutic values are bestowed on the repopulated microglia given their strong self-renewal capacity and highly proliferative and migratory abilities. In this paper, we first provide a comprehensive summary of the exploration process concerning the origin, development, repopulation, and heterogeneity of microglia. Moreover, we emphasize the implications of microglial repopulation in CNS disorders in the era of single-cell to enhance the understanding of microglial repopulation and provide more insights for new therapeutic strategies.

Keywords:  CNS disorders; CSF1R; Microglia; Repopulation; scRNA-seq

DOI:  https://doi.org/10.1016/j.nbd.2025.107066
Transl Neurodegener. 2025 Aug 22. 14(1): 43

Cyclooxygenase-1 deletion in 5 × FAD mice protects against microglia-induced neuroinflammation and mitigates cognitive impairment.

Jie Wang, Hong Ni, Yu Wang, Luyao Wei, Hanqing Ding, Zhongzhao Guo, Hao Pan, Ying Yu, Jia Luo, Weidong Pan, Deheng Wang, Zun-Ji Ke.

   BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with major symptoms including memory and learning deficits. Neuroinflammation associated with reactive microglia promotes AD progression. These reactive microglia secrete prostaglandins, which are synthesized through the enzymatic activity of cyclooxygenase (COX)-1 and COX-2. Here, we aimed to elucidate the specific mechanisms of COX1 in AD pathogenesis and its interactions with neuroinflammatory processes.
METHODS: We conducted backcrossing between COX-1 knockout (KO) and 5 × FAD mice to evaluate the effect of COX-1 deficiency on neuroinflammation. In addition, single-cell sequencing and microarray datasets from public databases and ingenuity pathway analysis in vitro were employed to explore gene expression profiles in the brains of AD mice.
RESULTS: We identified a significant upregulation of COX-1 in 5 × FAD mice, with expression specifically localized to microglia in an age-dependent manner. Additionally, COX-1 KO alleviated neuroinflammation and accumulation of Aβ plaques, subsequently improving cognitive behavior in 5 × FAD mice. Moreover, microglia exhibited an amoeboid morphology in 5 × FAD mice, whereas in age-matched 5 × FAD/COX-1 KO mice, microglia had a ramified appearance. Additionally, our study demonstrated a pharmacological approach that inhibits the prostaglandin E2 (PGE2)/EP2 receptors via inhibition of the cAMP-PKA-NFκB-p65 pathway and NLRP3 inflammasome activation, producing similar beneficial effects as observed in COX-1 KO mice.
CONCLUSION: Our findings indicate that targeting the COX-1/PGE2/EP2 signaling pathway may alleviate neuroinflammation and impede AD progression. Moreover, the EP2 receptor presents a promising pharmacological target for mitigating the pathological effects associated with COX-1 activity in AD patients.

Keywords:  Alzheimer’s disease; Cognitive impairment; Cyclooxygenase-1; Microglia; NLRP3 inflammasome; Neuroinflammation

DOI:  https://doi.org/10.1186/s40035-025-00501-9
Nat Commun. 2025 Aug 27. 16(1): 7994

Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health.

Kate I Tsourmas, Claire A Butler, Nellie E Kwang, Zachary R Sloane, Koby J G Dykman, Ghassan O Maloof, Biswa P Choudhury, Mousumi Paulchakrabarti, Christiana A Prekopa, Emily Z Tabaie, Robert P Krattli, Sanad M El-Khatib, Vivek Swarup, Munjal M Acharya, Lindsay A Hohsfield, Kim N Green.

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme (Hexb). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To investigate how a microglial gene is involved in neuronal homeostasis, here we show that β-hexosaminidase is secreted by microglia and integrated into the lysosomal compartment of neurons. To assess therapeutic relevance, we treat the Hexb-/- SD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces Hexb-/- microglia with Hexb-sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores β-hexosaminidase enzymatic activity and Hexb expression, prevents substrate buildup, and normalizes neuronal lysosomal phenotypes, underscoring the critical role of myeloid-derived β-hexosaminidase in maintaining neuronal health and establishing microglial replacement as a potential LSD therapy.

DOI: https://doi.org/10.1038/s41467-025-63237-0
J Neurochem. 2025 Aug;169(8): e70188

TREM2 and Pain Development: An Old Molecule, a New Target.

Zhenzhen Fan, Chenshu Huang, Xu Li, Rong Pan, Hongbin Cai, Xiaobin Zhai, Zhaoming Ge, Songtang Sun.

  The essence of pain involves a multi-system interaction encompassing sensation, emotion, and cognition, with multi-level regulatory mechanisms such as peripheral sensitization, central plasticity, neuroimmune signal crosstalk, and glial cell activation playing critical roles. Among these mechanisms, microglia, as the primary immune effector cells in the central nervous system, contribute significantly to chronic pain by releasing pro-inflammatory factors and modulating synaptic remodeling. Nevertheless, significant gaps remain in our current understanding, including the molecular switch governing the transition from acute to chronic pain, the precise mechanisms regulating microglial phenotypic conversion, and the biological basis of endogenous pain resolution pathways. In this context, the triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a focal point of research due to its multifaceted regulation of microglial functions and its dual role in neuroimmune modulation. TREM2 dynamically balances pro-inflammatory and anti-inflammatory signals by modulating the complement system, regulating phagocytosis-related gene expression, and maintaining lipid metabolism homeostasis. While suppressing excessive inflammatory responses, TREM2 may also impair immune surveillance and potentially drive disease progression. However, significant gaps remain in our understanding of the specific mechanisms underlying TREM2's role in pain. The spatiotemporal dynamics of TREM2 signaling pathways, gender-specific effects, and interactions with pain-associated immune cell subsets remain to be systematically elucidated. Notably, loss-of-function mutations in TREM2 may influence the pathological process of pain by altering ligand-binding affinity; however, the precise molecular mechanisms require further experimental validation. These unresolved scientific questions underscore the translational medicine potential of TREM2 as a novel analgesic target while also highlighting the existing translational gap between current basic research and clinical applications. This review aims to comprehensively describe how TREM2 contributes to neuropathic pain (NP), chemotherapy-induced peripheral neuropathy pain (CIPN), inflammatory pain, and migraine, thereby providing theoretical support for developing novel analgesic drugs targeting TREM2.

Keywords:  TREM2; chemotherapy‐induced peripheral neuralgia; inflammatory pain; microglia; migraine; neuropathic pain

DOI:  https://doi.org/10.1111/jnc.70188
J Neurochem. 2025 Aug;169(8): e70209

The Multifaceted Role of Extracellular Vesicles in Alzheimer's Disease.

Anna R R Da Conceicao, Júlia Marinatto, Lisandra S Pinheiro, Tayna Rody, Fernanda G De Felice.

  Extracellular vesicles (EVs) are lipid bilayer nano- to micro-sized particles that carry biomolecules, such as proteins, lipids, and genetic material. Their composition depends on the cellular microenvironment and the health status of tissues. EVs are released by different cell types under distinct circumstances, mediating intercellular communication in both physiological and pathological contexts. In Alzheimer's disease (AD), EVs have been shown to influence pathological events, carrying neurotoxins, such as neuroinflammatory factors, pathogenic forms of amyloid-β, and phosphorylated tau into recipient neurons. This contributes to the propagation of AD pathology and exacerbates neuronal degeneration. However, under physiological conditions, EVs play key roles in maintaining tissue homeostasis. In the central nervous system (CNS), EVs derived from glial cells and neurons modulate synaptic plasticity and neuronal activity. Interestingly, EVs carrying neurotoxin molecules can cross the blood-brain barrier, making them attractive candidates as biomarkers for diagnosis with a minimally invasive approach to assess CNS alterations. Additionally, EVs contribute to the activation of neuroprotective pathways, participating in the periphery-to-brain signaling. Notably, alteration of EV content has been further proposed to have potential therapeutic applications. Herein, we summarize the multifaceted role of EVs in AD, emphasizing their role in promoting neuroprotection and exploring their contribution to our understanding of AD pathophysiology.

Keywords:  Alzheimer's disease; biomarkers; extracellular vesicles; neuroinflammation; neuroprotection

DOI:  https://doi.org/10.1111/jnc.70209
J Cell Physiol. 2025 Aug;240(8): e70086

Connexin 43 Role in Mitochondrial Transfer and Homeostasis in the Central Nervous System.

Anna Gervasi, Simona D'Aprile, Simona Denaro, Maria Angela Amorini, Nunzio Vicario, Rosalba Parenti.

  Connexin 43 (Cx43) is a transmembrane protein involved in the assembly of gap junctions (GJs) and hemichannels (HCs), organized structures that allow the transferring of ions and small signaling molecules between cells and/or extracellular environment, thereby contributing to tissue homeostasis intercellular communication. Cx43 has recently been identified within the mitochondria of cells, suggesting that it may have additional functions beyond its canonical role. Most studies of mitochondrial Cx43 (mt-Cx43) have been limited to cells of the cardiovascular system, where it appears to play a role in ATP production, calcium homeostasis, and the response to oxidative stress. However, its functions within the central nervous system (CNS) are not fully understood. Recently, it has been observed that Cx43-forming GJs is one of the key mechanisms that cells use for the transfer of organelles, including mitochondria. Cx43-mediated mitochondrial transfer is crucial in the CNS, supporting cellular homeostasis and neuroprotection under both physiological and pathological conditions. The dual roles of Cx43 in regulating mitochondrial function and in mediating mitochondrial transfer, raise important questions about how it coordinates these mechanisms. Herein, we reviewed recent findings on the importance of Cx43 and mt-Cx43 in the healthy and altered CNS environment, with the aim of shedding light on its potential role in CNS homeostasis and as a therapeutic target in neurological disorder in which Cx43 plays a predominant function.

Keywords:  gap junction; homeostasis; intercellular communication; metabolism; neurological disorder

DOI:  https://doi.org/10.1002/jcp.70086
Nat Commun. 2025 Aug 26. 16(1): 7951

ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.

Isadora Lenoel, Matthieu Ribon, Félicie Lorenc, Aurélien Diebold, Clementine E Philibert, David Robaldo, Manel Badsi, Julianne Perronnet, Julie Lameth, Felix Berriat, Hidemi Misawa, Marie Coutelier, Raphaelle Cassel, Nadège Sarrazin, Coline Jost-Mousseau, Delphine Bohl, Stéphanie Millecamps, Michel Mallat, David Brenner, Jochen H Weishaupt, Séverine Boillée, Christian S Lobsiger.

TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 have been linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD), and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of TBK1 mutations. Here, we show that deleting Tbk1 from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, Tbk1 deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, Tbk1 deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial Tbk1 deletion is sufficient to cause early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra pars reticulata and pallidum. Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction.

DOI: https://doi.org/10.1038/s41467-025-63211-w
ACS Chem Neurosci. 2025 Aug 27.

Modulation of Amyloid-β Aggregation by Surface Proteins from Pathogens Associated with Alzheimer's Disease.

Antonin Kunka, Hana Hribkova, Tereza Vanova, Veronika Pospisilova, Martin Havlasek, Jan Haviernik, Daniel Ruzek, Jiri Damborsky, Dasa Bohaciakova, Zbynek Prokop.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. Despite substantial research efforts, our understanding of its pathogenesis remains incomplete, limiting the development of effective treatments and preventive strategies. The potential role of microbial pathogens in AD etiology has gained increasing attention. Various human microbial pathogens have been identified in the brains of AD patients, leading to the pathogen hypothesis, which posits that these microorganisms may disrupt the brain's immune regulation and homeostasis. In this study, we examine the effects of proteins from three pathogens, Borrelia burgdorferi, HSV-1, and Porphyromonas gingivalis, on the aggregation of antimicrobial peptide amyloid-β (Aβ). Three of the four studied proteins were found to attenuate the aggregation of Aβ42 by interacting with its soluble form and inhibiting primary and secondary pathways. These in vitro findings were further supported by experiments using mature neurons derived from human pluripotent stem cells, which showed an increased accumulation of amyloid precursor protein (APP) aggregates upon infection with HSV-1 or exposure to the OspA surface protein from B. burgdorferi. Together, our results provide mechanistic insights into how pathogen-associated proteins modulate Aβ42 aggregation, contributing to an understanding of their potential role in AD pathogenesis.

Keywords:  Alzheimer’s disease; amyloid-β; amyloids; neuroinflammation; pathogen; virus

DOI:  https://doi.org/10.1021/acschemneuro.5c00444
Elife. 2025 Aug 27. pii: RP99344. [Epub ahead of print]13

Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells.

Yuqing Zhu, Kevin Cho, Haluk Lacin, Yi Zhu, Jose T DiPaola, Beth A Wilson, Gary Patti, James B Skeath.

  Dihydroceramide desaturases convert dihydroceramides to ceramides, the precursors of all complex sphingolipids. Reduction of DEGS1 dihydroceramide desaturase function causes pediatric neurodegenerative disorder hypomyelinating leukodystrophy-18 (HLD-18). We discovered that infertile crescent (ifc), the Drosophila DEGS1 homolog, is expressed primarily in glial cells to promote CNS development by guarding against neurodegeneration. Loss of ifc causes massive dihydroceramide accumulation and severe morphological defects in cortex glia, including endoplasmic reticulum (ER) expansion, failure of neuronal ensheathment, and lipid droplet depletion. RNAi knockdown of the upstream ceramide synthase schlank in glia of ifc mutants rescues ER expansion, suggesting dihydroceramide accumulation in the ER drives this phenotype. RNAi knockdown of ifc in glia but not neurons drives neuronal cell death, suggesting that ifc function in glia promotes neuronal survival. Our work identifies glia as the primary site of disease progression in HLD-18 and may inform on juvenile forms of ALS, which also feature elevated dihydroceramide levels.

Keywords:  D. melanogaster; DEGS1; ceramide; developmental biology; glial cell; leukodystrophy; neurodegeneration; sphingolipids

DOI:  https://doi.org/10.7554/eLife.99344
Cell Death Dis. 2025 Aug 25. 16(1): 643

Neutrophils-astrocyte interactions in central nervous system inflammation.

Bingyou Yuan, Xian Zhang, Liang Liu, Yan Chai, Jianning Zhang, Xin Chen.

The concept of central nervous system (CNS) "immune privilege" has undergone substantial revision. We now understand that the CNS exhibits sophisticated inflammatory responses that serve dual functions: potentially detrimental in acute phases while facilitating repair and recovery during chronic stages of various neurological conditions. Recent advances in genomic technologies, particularly high-throughput single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, have revolutionized our understanding of cellular dynamics and interactions within the CNS inflammatory microenvironment. Here, we examine the intricate interplay between neutrophils and astrocytes during CNS inflammation. We synthesize emerging evidence of their reciprocal regulation, analyze their roles in neurological diseases, and delineate the molecular pathways mediating their communication. Understanding these cellular interactions could reveal promising therapeutic targets for modulating secondary CNS inflammation, potentially leading to more effective treatment strategies for neurological disorders.

DOI: https://doi.org/10.1038/s41419-025-07945-x
J Exp Med. 2025 Oct 06. pii: e20250965. [Epub ahead of print]222(10):

ApoE-calypse tau: ApoE-tau synergy in Alzheimer's disease.

Matthew Paul Lennol, Chiara Bordier, Léana Kamelher, Jason D Ulrich, David M Holtzman, Maud Gratuze.

Alzheimer's disease (AD), the most common cause of dementia, is characterized by the accumulation of amyloid-β (Aβ) in senile plaques and abnormally hyperphosphorylated tau proteins in neurofibrillary tangles. While much of the research has focused on Aβ, tau-mediated neurodegeneration is more closely associated with synaptic loss and cognitive decline in AD, emphasizing the need for a deeper understanding of tau pathology. In this context, the interaction between tau and APOE, particularly the main genetic risk factor for AD APOE ε4, remains underexplored. APOE encodes apolipoprotein E (apoE), a protein important in lipid metabolism. In addition to promoting Aβ deposition, emerging evidence suggests that APOE ε4 exacerbates tau-mediated neurodegeneration and tau-related pathology. This review consolidates current knowledge on the interplay between apoE and tau, highlighting its potential as a key factor in disease progression. Targeting the apoE-tau axis may offer promising therapeutic strategies to address the molecular mechanisms driving AD and primary tauopathies.

DOI: https://doi.org/10.1084/jem.20250965
EMBO J. 2025 Aug 26.

RABGAP1 is a sensor that facilitates the sorting and processing of amyloid precursor protein.

Jessica Eden, Jonathan G G Kaufman, Conceição Pereira, Eleanor Fox, Jerome Cattin-Ortolá, Lorena Benedetti, Bart Nieuwenhuis, David J Owen, Jennifer Lippincott-Schwartz, Sean Munro, David C Gershlick.

  A hallmark of Alzheimer's disease (AD) is the accumulation of extracellular amyloid-β plaques in the brain. Amyloid-β is a 40-42 amino acid peptide generated by proteolytic processing of amyloid precursor protein (APP) via membrane-bound proteases. APP is a transmembrane protein, and its trafficking to sites of proteolysis represents a rate-limiting step in AD progression. Although APP processing has been well-studied, its trafficking itinerary and machinery remain incompletely understood. To address this, we performed an unbiased interaction screen for interactors of the APP cytosolic tail. We identified previously characterised APP binders as well as novel interactors, including RABGAP1. We demonstrated that RABGAP1 partially co-localises with APP and directly interacts with a YENPTY motif in the APP cytosolic tail. Depletion or overexpression of RABGAP1 caused mistrafficking and misprocessing of endogenous APP in human and rodent neurons. This effect is dependent on the GAP activity of RABGAP1, demonstrating that RABGAP1 affects the trafficking of APP by modulating RAB activity on endosomal subdomains. This novel trafficking mechanism has implications for other NPXY cargoes and presents a possible therapeutic avenue to explore.

Keywords:  APP; Alzheimer’s Disease; RABGAP1; Trafficking

DOI:  https://doi.org/10.1038/s44318-025-00530-0
Neurobiol Dis. 2025 Aug 18. pii: S0969-9961(25)00274-8. [Epub ahead of print]215 107058

Extracellular tau clearance is governed by its aggregation state and independent of microglial activation by LPS and IFN-γ.

Andrew Shultz, Anna Vincze, Todd T Yau, Emma L Poirier, Hannah Demanche, Jennifer N Rauch.

  Microglia are the tissue resident macrophages of the brain and their contribution to tau pathology progression remains to be fully understood. In this study, we developed a quantitative platform to elucidate the processing of extracellular tau within human induced pluripotent stem cell (iPSC)-derived microglia. We show that iPSC-derived microglia internalize monomeric and fibrillar tau through different cellular mechanisms and with different clearance kinetics. Acute inflammatory activation of microglia alters tau endocytosis, but surprisingly does not impact tau clearance. These results highlight the importance of the microglial endo-lysosome system as a regulator of tau pathology that is decoupled from acute microglial activation.

Keywords:  Endo-lysosomal dysfunction; Inflammation; LRP1; Microglia; Tau; Tau spread

DOI:  https://doi.org/10.1016/j.nbd.2025.107058
Sci Adv. 2025 Aug 22. 11(34): eadu2708

Understanding monocyte-driven neuroinflammation in Alzheimer's disease using human cortical organoid microphysiological systems.

Chunhui Tian, Zheng Ao, Jonas Cerneckis, Hongwei Cai, Lei Chen, Hengyao Niu, Kazuo Takayama, Jungsu Kim, Yanhong Shi, Mingxia Gu, Takahisa Kanekiyo, Feng Guo.

Increasing evidence strongly links neuroinflammation to Alzheimer's disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability. Using these models, we found that monocytes from AD patients exhibit increased infiltration ability, decreased amyloid-β clearance capacity, and stronger inflammatory response than monocytes from age-matched control donors. Moreover, we observed that AD monocytes induce pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis. Furthermore, the marked increase in IL1B and CCL3 expression underscores their pivotal role in AD monocyte-mediated neuroinflammation. Our findings provide insight into understanding monocytes' role in AD pathogenesis, and our lab-compatible MPS models may offer a promising way for studying various neuroinflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.adu2708
Neurobiol Dis. 2025 Aug 18. pii: S0969-9961(25)00273-6. [Epub ahead of print]215 107057

Retinal tau phosphorylation in Alzheimer's disease: A mass spectrometry study.

Netherlands Brain Bank

   INTRODUCTION: Most neurodegenerative diseases, including Alzheimer's disease (AD) and multiple sclerosis (MS), feature abnormal tau phosphorylation (p-tau) in the brain. Prior immunostaining studies have shown p-tau accumulation in the AD retina, suggesting it may mirror brain tau pathology.
METHODS: We used mass spectrometry to quantify p-tau peptides in matched retinal and hippocampal samples from non-demented controls (NC, n = 8), AD (n = 12), and MS (n = 4). We compared p-tau levels across diagnoses and analysed correlations between retinal p-tau variants, hippocampal p-tau, and neuropathological changes.
RESULTS: Tau peptides phosphorylated at T181, S199/S202, T231, T231 + T235, S396 + T403/S404, and T403/S404 were detected in retinas. Total tau phosphorylation and phosphorylation at S199/S202 and T231 were significantly higher in AD cases compared to NC. These two, along with p-tau S396 + T403/S404, were also higher in cases with high amyloid-beta (Aβ) Braak stages compared to those with low Aβ Braak stages. Higher Aβ stages were also correlated with higher peak intensities of p-tau S199/S202 and S396 + T403/S404, and retinal p-tau S396 + T403/S404 and T403/S404 correlated with neurofibrillary tangle (NFT) Braak stages. Additionally, p-tau S396 + T403/S404 in the retina was associated with corresponding phosphorylation in the hippocampus.
CONCLUSION: Our findings reveal both overlapping and distinct p-tau patterns in retina and hippocampus, with a notable link for p-tau S396 + T403/S404. This enhances our understanding of tauopathies in both tissues and supports retinal tau as a promising biomarker for AD diagnosis and monitoring.

Keywords:  Alzheimer's disease; Mass spectrometry; P-tau; Retina; Tau

DOI:  https://doi.org/10.1016/j.nbd.2025.107057
J Neurosci. 2025 Aug 20. pii: e0383252025. [Epub ahead of print]

IGFBP2-Ceramides Pathway Mediates Divergent Myelin Breakdown in the PNS and CNS Following Injury.

Suchen Ma, Xinman Fu, Jinmeng Lyu, Weilin Guo, Zhengxin Ying.

Following injury, the peripheral nervous system (PNS) exhibits remarkable regenerative capacity, whereas the central nervous system (CNS) has limited regenerative potential. This difference is partially attributed to distinct post-injury myelin breakdown. However, the underlying mechanisms driving this disparity remain unclear. By comparing the expression profiles of injured peripheral and central nerves in adult male and female C57BL/6J mice, we identified IGFBP2 as a key regulator that determines the differences in myelin breakdown between the injured PNS and CNS. Schwann cell-derived IGFBP2 in the injured PNS promotes myelin breakdown and facilitates axonal regeneration. Furthermore, through lipidomics, we identify ceramide, a sphingolipid regulated by ceramide synthase 6 in injured nerves, as playing a critical role in IGFBP2-mediated myelin breakdown. Conversely, minimal IGFBP2 expression is observed in the injured CNS, contributing to the limited myelin breakdown and axon regeneration in injured CNS. These findings provide insights into the divergent regenerative potential of the PNS and CNS and unveil IGFBP2 and ceramide as promising targets for promoting CNS regeneration after injury.Significance Statement Our research sheds light on the contrasting regenerative capacities of the peripheral nervous system (PNS) and central nervous system (CNS) after injury. Understanding why the PNS exhibits robust regeneration while the CNS does not could revolutionize treatments for neurological injuries and diseases. We discovered that Schwann cell-derived IGFBP2 plays a crucial role in promoting myelin breakdown and axon regeneration in the PNS. Moreover, our findings highlight the involvement of ceramide, a lipid molecule, in this process. Identifying these key players not only deepens our understanding of nerve regeneration but also unveils potential targets for therapeutic interventions aimed at enhancing CNS regeneration post-injury.

DOI: https://doi.org/10.1523/JNEUROSCI.0383-25.2025