bims-micgli 2025-09-07 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–09–07
twenty-one papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Enriched Environment Alleviate AD Pathological Progression by Reducing Microglia Complement Signaling in Aged Male APP/PS1 Mice.
Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras.
Microglia and Chek2 contribute to sex-specific organization of the adult zebrafish brain.
Role of mTORC1 signaling in postnatal microglia activation preceding neurodegeneration in a mouse model for Niemann-Pick disease Type C.
Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.
Isotope-encoded spatial biology identifies plaque-age-dependent maturation and synaptic loss in an Alzheimer's disease mouse model.
Amyloid β interaction with membranes: Removal of cholesterol from the membranes to catalyze aggregation and amyloid pathology.
Hemispheric asymmetry of tau pathology is related to asymmetric amyloid deposition in Alzheimer's Disease.
The human microglia responsome: a resource for microglia states in health and disease.
TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects.
MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.
Alzheimer Disease: The proposed role of tanycytes in the formation of tau tangles and amyloid beta plaques in human brain.
Amyloid β-dependent neuronal silencing through synaptic decoupling.
Deficiency of Microglial Hv1 Protects Against Lipopolysaccharide-Induced Neuroinflammation via the NF-κB Signaling Pathway and HIF1α-Mediated Metabolic Reprogramming.
Emerging roles for innate and adaptive immunity in tauopathies.
STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome.
Down syndrome and a presenilin 2 variant: dual genetic risk of Alzheimer's disease.
Dual Pro-Angiogenic and Pro-Fibrotic MARCO+ Microglial Phenotype in Diabetic Retinopathy.
Identification and validation of a tear fluid-derived protein biomarker signature in patients with amyotrophic lateral sclerosis.
Enhancing microglial antioxidant capacity via the ascorbate transporter SVCT2 delays onset and modifies disease progression in mouse models of Alzheimer's disease.
Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits.

FASEB J. 2025 Sep 15. 39(17): e71026

Enriched Environment Alleviate AD Pathological Progression by Reducing Microglia Complement Signaling in Aged Male APP/PS1 Mice.

Hai-Chao Chen, Jia-Xin Cao, Yi-Shu Zhang, Xiao-Mei Su, Yi-Ting Kang, Li-Ping Gao, Yu-Hong Jing.

  Alzheimer's disease (AD) is influenced by genetic and environmental factors. Previous studies showed that enriched environments improved memory and reduced amyloid plaques in AD mice, but the underlying mechanisms remain unclear. This study investigated the effects and mechanisms of enriched environments on AD pathology and cognitive function in aged APP/PS1 mice. Male APP/PS1 mice (15 months old) and wild-type littermates were divided into four groups: WT/SE, WT/EE, Tg/SE, and Tg/EE. Mice in EE groups were subjected to intervention with enriched environment for a period of 5 months. Results showed that enriched environments preserved cognitive function, reduced Aβ and p-Tau aggregation, and mitigated microglial inflammation (Tlr-4, NF-κB, iNOS). They also decreased C1q expression and slowed dendritic spine loss in hippocampal granule cells of APP/PS1 mice. These findings suggest that enriched environments can slow AD progression by regulating microglial inflammation and maintaining neuronal integrity, particularly in hippocampal dendritic spines.

Keywords:  Alzheimer' disease; C1q; amyloid‐β; enriched environment; microglial; synapse loss

DOI:  https://doi.org/10.1096/fj.202501545RR
Nat Commun. 2025 Aug 30. 16(1): 8128

Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras.

Youqiao Wang, Zeyi Wang, Ziyi Liu, Jinyan Li, Shuo Yang, Yuxuan Zhao, Yangmei Huang, Chenyang Liao, Yiqiu Zhang, Jiaojiao Zhao, Weilin Zhou, Binhua Zhou, Xin Yue, Qiang Zhou, Xianzhang Bu.

Amyloid-β (Aβ), a key driver of Alzheimer's disease (AD) pathogenesis, possesses diverse harmful and clearance-resistant structures that present substantial challenges to therapeutic development. Here, we demonstrate that modulating Aβ morphology, rather than Toll-like receptor 2 (TLR2)-dependent microglia activation, is essential for effective phagocytosis of Aβ species by microglia. By developing a bifunctional mechanistic probe (P2CSKn) designed to remodel Aβ and activate TLR2, we show it restructures soluble Aβ (sAβ) and fibrillar Aβ (fAβ) into less toxic hybrid aggregates (hPAβ). Critically, this structural remodeling protects microglia from Aβ toxicity while enabling robust phagocytosis. Moreover, although TLR2 activation mildly enhances Aβ uptake, it concurrently triggers detrimental inflammation that negates its benefits. Our findings establish morphological remodeling as the critical determinant of effective Aβ clearance and suggest a morphology-focused strategy for developing safe therapeutics for Aβ-related diseases.

DOI: https://doi.org/10.1038/s41467-025-63458-3
bioRxiv. 2025 Aug 21. pii: 2025.08.15.670359. [Epub ahead of print]

Microglia and Chek2 contribute to sex-specific organization of the adult zebrafish brain.

Paloma Bravo, Florence L Marlow.

Sex specific differences in size and distribution of cell types have been observed in mammalian brains. How sex-specific differences in the brain are established and to what extent sexual dimorphism contributes to sex-biased neurodevelopment and neurological disorders is not well understood. Microglia are the resident immune cells of the nervous system and have been implicated in masculinizing the mammalian brain and refining neural connections to promote remodeling of neural circuitry, yet their contributions to developmental brain patterning and plasticity in zebrafish remains unclear. Here, we report anatomical and cellular differences between juvenile brains and adult female and male brains. Leveraging the plasticity of the zebrafish female brain and genetic models lacking microglia and tumor suppressor factors, we provide insight into the mechanisms that establish sex-specific brain dimorphism in zebrafish. Specifically, we identified sexually dimorphic features in the adult zebrafish brain that depend on microglia and Chek2, which may have broader implications and represent therapeutic targets for sex-biased neurological disorders.
Plain language summary: Males and females of species can have significant differences in appearance, including differences in size, color, or sex specific anatomical structures. In addition to overt morphological differences, sex specific differences in size and distribution of cell types have been observed in mammalian brains. How these sex-specific differences in the brain are established and to what extent these differences contribute to sex-specific neurodevelopment and neurological disorders that differentially impact males and females is not well understood. Despite an incomplete picture of the mechanisms regulating sex-specific development, some of the cell types involved include microglia. Microglia are the resident immune cells of the nervous system and have been implicated in promoting features that are typical in the male mammalian brain. Specifically, microglia may refine neural connections and promote remodeling of neural circuitry and influence sex-specific behaviors. The contributions of microglia to developmental brain patterning and plasticity in zebrafish remain unclear. Here, we report anatomical and cellular differences between juvenile brains and adult female and male brains. Leveraging zebrafish genetic models lacking microglia and tumor suppressor factors, and the unique plasticity of the zebrafish female brain, we investigated and provide insight into the mechanisms that establish sex-specific brain differences in zebrafish. Specifically, we identified sexually distinct features in the adult zebrafish brain that depend on microglia and the tumor suppressor Chek2. If these or similar mechanisms operate in other species, our findings may have broader implications for sex-specific brain development and represent therapeutic targets for sex-biased neurological disorders.
Highlights: Tissue clearing and immunostaining of juvenile and adult whole-mount zebrafish brains allows analysis of sex differences.Anatomical and cellular sexual dimorphism in the adult vertebrate brain appears after gonadal sex differentiation.Sexual dimorphism in the adult brain is driven by differences in cell death regulation.Microglia colonization of brain areas involved in courtship is sexually dimorphic.Microglia involvement in establishing sex-specific differences in the adult brain.

DOI: https://doi.org/10.1101/2025.08.15.670359
PLoS One. 2025 ;20(9): e0330437

Role of mTORC1 signaling in postnatal microglia activation preceding neurodegeneration in a mouse model for Niemann-Pick disease Type C.

Caroline E Murray, David S Betancourt-Trompa, Michael S Martinez, Julia M Carson, Lindsay J Walsh, Will C Remillard, Kayla B Fordyce, Rohan Reddy, Ileana Soto.

In Npc1 deficient mice, postnatal developmental alterations in cerebellar microglia and Purkinje cells (PCs) are followed by early-onset neurodegeneration. Even in the absence of PC loss, microglia in Npc1nmf164 mice display hallmark features of activation during early postnatal development, including increased proliferation, enhanced phagocytic activity, and morphological changes indicative of an activated state. In this study, we investigated whether mammalian target of rapamycin complex 1 (mTORC1) drives postnatal activation of cerebellar microglia in Npc1nmf164 mice. We found that elevated CLEC7A (Dectin-1) expression and phosphorylation of S6 ribosomal protein (pS6R), a downstream target of mTORC1, co-occurred in microglial precursors within the developing white matter region (dWMR) of wild-type (WT) mice at postnatal day 7 (P7), as well as in neurodegeneration-associated microglia located in the molecular layer (ML) of Npc1nmf164 mice at P60. In contrast, microglia in the WMR of Npc1nmf164 mice at P60 did not show evidence of CLEC7A expression or increased mTORC1 activation. Interestingly, microglial precursors in the dWMR of Npc1nmf164 mice did not exhibit increased mTORC1 activation at P7 but instead showed delayed increased activation at P10. Inhibiting mTORC1 signaling with rapamycin from P10 to P21 reduced both microglial proliferation and soma size in Npc1nmf164 mice. Additionally, rapamycin treatment preserved VGLUT2⁺ presynaptic terminals/axons that innervate PC dendrites and decreased the total volume of CD68⁺ phagosomes per microglial cell, suggesting a reduction in phagocytic activity. However, the volume of VGLUT2⁺ synaptic material per phagosome remained unchanged between vehicle- and rapamycin-treated groups. While rapamycin enhanced myelination in Npc1nmf164 mice, it did not alter microglial phenotypes in the cerebellar WMR, suggesting that mTORC1 signaling does not mediate WMR microglial activation in this model. Together, our findings demonstrate that mTORC1 activation contributes to the aberrant activation of postnatal ML microglia and to early cerebellar pathology in Npc1nmf164 mice.

DOI: https://doi.org/10.1371/journal.pone.0330437
Neurochem Res. 2025 Sep 05. 50(5): 287

Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.

Jialei Qian, Shengyuan Ren, Tianning Ren, Renke Shi, Liang Qiao, Jing Kang.

  Astrocytes, the most abundant and functionally diverse glial cell type in the brain, play a crucial role in maintaining cellular homeostasis and promoting neuronal survival. Autophagy is the process of transferring senescent, denatured, or damaged proteins and organelles from cells to lysosomes for degradation. However, recent research on autophagy in the central nervous system has focused on neurons. In this paper, we reviewed the latest findings on astrocyte autophagy and its mechanisms in regulating neurodegenerative disorders. It influences the pathological processes of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other synucleinopathies (including dementia with Lewy bodies and Parkinson's disease dementia) by regulating oxidative stress and inflammatory responses, as well as aberrant protein aggregation and folding. Furthermore, we listed medications that can prevent or treat neurodegenerative disorders by modulating astrocyte autophagy pathways, providing new insights into preventive and therapeutic strategies for neurodegenerative diseases.

Keywords:  Astrocytes; Autophagy; Mechanism; Neurodegenerative disorders; Treatment

DOI:  https://doi.org/10.1007/s11064-025-04532-6
Nat Commun. 2025 Sep 01. 16(1): 8170

Isotope-encoded spatial biology identifies plaque-age-dependent maturation and synaptic loss in an Alzheimer's disease mouse model.

Jack I Wood, Maciej Dulewicz, Alicja Szadziewska, Sophia Weiner, Junyue Ge, Katie Stringer, Sneha Desai, Lydia Fenson, Diana Piotrowska, Gunnar Brinkmalm, Srinivas Koutarapu, Haady B Hajar, Kaj Blennow, Henrik Zetterberg, Damian M Cummings, Jeffrey N Savas, Frances A Edwards, Jörg Hanrieder.

Understanding how amyloid beta (Aβ) plaques develop and lead to neurotoxicity in Alzheimer's disease remains a major challenge, particularly given the temporal delay and weak correlation between plaque deposition and cognitive decline. This study investigates how the evolving pathology of plaques affects the surrounding tissue, using a knock-in Aβ mouse model (AppNL-F/NL-F). We combined mass spectrometry imaging with stable isotope labeling to timestamp Aβ plaques from the moment of their initial deposition, enabling us to track their aging spatially. By integrating spatial transcriptomics, we linked changes in gene expression to the age of the plaques, independent of the mice's chronological age or disease stage. Here we show that older plaques were associated with reduced expression of synaptic genes. Additionally, when correlated with structure-specific dyes, we show that plaque age positively correlated with structural maturation. These more compact and older plaques were linked to greater synapse loss and increased toxicity.

DOI: https://doi.org/10.1038/s41467-025-63328-y
bioRxiv. 2025 Aug 24. pii: 2025.08.20.671368. [Epub ahead of print]

Amyloid β interaction with membranes: Removal of cholesterol from the membranes to catalyze aggregation and amyloid pathology.

Rishiram Baral, Ruan van Deventer, Yuri L Lyubchenko.

The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42- residue form of the amyloid-β peptide) peptides in pathological aggregates is considered as one of the major molecular mechanisms in development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that the high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability of monomeric Aβ42. Extracted cholesterol interacts with Aβ42 and accelerates its on- membrane aggregation. We propose a model of interaction of Aβ42 with membranes based on the ability of Aβ42 to extract cholesterol, which explains several AD associated observations related to cholesterol interplay with Aβ42 aggregation resulting in the AD onset and progression.

DOI: https://doi.org/10.1101/2025.08.20.671368
Nat Commun. 2025 Sep 05. 16(1): 8232

Hemispheric asymmetry of tau pathology is related to asymmetric amyloid deposition in Alzheimer's Disease.

Alzheimer’s Disease Neuroimaging Initiative

The distribution of tau pathology in Alzheimer's disease (AD) shows remarkable inter-individual heterogeneity, including hemispheric asymmetry. However, the factors driving this asymmetry remain poorly understood. Here we explore whether tau asymmetry is linked to i) reduced inter-hemispheric brain connectivity (potentially restricting tau spread), or ii) asymmetry in amyloid-beta (Aβ) distribution (indicating greater hemisphere-specific vulnerability to AD pathology). We include 452 participants from the Swedish BioFINDER-2 cohort with evidence of both Aβ pathology (CSF Aβ42/40 or neocortical Aβ-PET) and tau pathology (temporal tau-PET), categorising them as left asymmetric (n = 102), symmetric (n = 306), or right asymmetric (n = 44) based on temporal lobe tau-PET uptake distribution. We assess edge-wise inter-hemispheric functional (RSfMRI; n = 318) and structural connectivity (dMRI; n = 352) but find no association between tau asymmetry and connectivity. In contrast, we observe a strong association between tau and Aβ laterality patterns based on PET uptake (n = 233; β = 0.632, p < 0.001), which we replicate in three independent cohorts (n = 234; β = 0.535, p < 0.001). In a longitudinal Aβ-positive sample, we show that baseline Aβ asymmetry predicts progression of tau laterality over time (n = 289; β = 0.025, p = 0.028). These findings suggest that tau asymmetry is not associated with a weaker inter-hemispheric connectivity but might reflect hemispheric differences in vulnerability to Aβ pathology, underscoring the role of regional vulnerability in determining the distribution of AD pathology.

DOI: https://doi.org/10.1038/s41467-025-63564-2
Brain Behav Immun. 2025 Sep 01. pii: S0889-1591(25)00330-7. [Epub ahead of print] 106095

The human microglia responsome: a resource for microglia states in health and disease.

Gijsje J L J Snijders, Katia de Paiva Lopes, Marjolein A M Sneeboer, Benjamin Z Muller, Frederieke A J Gigase, Dante D'Urso, Ricardo A Vialle, Roy Missall, Raphael Kubler, Towfique Raj, Jack Humphrey, Lot D de Witte.

  Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human enriched microglial cells from 67 different donors (N = 398 samples, primarily aged >60 years) at the gene and transcript level. We show that enriched microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We define specific enriched microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimer's disease (AD) (genetic) studies and enriched microglia. Together, we provide a comprehensive transcriptomic resource of the human microglia responsome.

Keywords:  Disease; Inflammatory triggers; Microglia

DOI:  https://doi.org/10.1016/j.bbi.2025.106095
Acta Neuropathol. 2025 Sep 04. 150(1): 23

TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects.

Irene García-Toledo, Juan M Godoy-Corchuelo, Luis C Fernández-Beltrán, Zeinab Ali, Ariadna Guindo-Arroyo, Irene Jiménez-Coca, Jesús Jiménez-Rodríguez, Karen Javaloyes-García, Marcos Viñuela, Ulises Gómez-Pinedo, Laura Saiz-Aúz, Alberto Rábano, Estela Área-Gómez, Thomas J Cunningham, Silvia Corrochano.

  TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the TardbpM323K/M323K knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.

Keywords:  Cholesterol metabolism; Lipid droplets; Lipidomics; Myelin; TDP-43 proteinopathies; Transcriptomics

DOI:  https://doi.org/10.1007/s00401-025-02927-x
Mol Neurodegener. 2025 Aug 28. 20(1): 94

MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.

Hai-Shan Jiao, Yi-Jun Ge, Liang-Yu Huang, Ying Liu, Bang-Sheng Wu, Piao-Piao Lian, Yi-Ning Hao, Shan-Shan Han, Yi-Ting Li, Kai-Min Wu, Chen-Yun Wu, Tian-Lin Cheng, Peng Yuan, Jin-Tai Yu.

   BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied.
METHODS: We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis.
RESULTS: We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures.
CONCLUSIONS: Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.

Keywords:  Alzheimer’s disease; MS4A6A; Microglia; Ms4a6d; Neuroinflammation

DOI:  https://doi.org/10.1186/s13024-025-00887-0
bioRxiv. 2025 Aug 28. pii: 2025.04.08.647836. [Epub ahead of print]

Alzheimer Disease: The proposed role of tanycytes in the formation of tau tangles and amyloid beta plaques in human brain.

Ruth Fabian-Fine, Abigail G Roman, Adam L Weaver.

Currently, the causes for Alzheimer Disease (AD) are thought to lie in the formation of abnormal protein deposits including tau tangles and Amyloid ß (Aβ) plaques in the human cortex. These proteins are believed to accumulate in the brain due to impaired waste removal resulting in neurodegeneration. In an alternative hypothesis we have recently proposed the existence of an aquaporin4 aqua channel (AQP4)-expressing tanycyte-derived canal network that likely internalizes waste for removal from the brain. We propose that both Aβ and tau protein may play important structural roles in this canal system. In support of this hypothesis, we demonstrate the formation of waste-internalizing receptacles by AQP4-expressing myelinated tanycytes. Using RNA-scope in situ hybridization, immunohistochemistry, ultrastructural, and histological approaches, we demonstrate receptacle differentiation in tanycyte-derived 'swell-bodies.' We show that these receptacles are AQP4- and Aβ-immunoreactive and that related gene expression is observed in 'swell-bodies' where receptacle differentiation is observed. Through correlative light- and electron-microscopy in human and mouse brain, we demonstrate that both Aß and tau protein are associated with these waste-internalizing structures (Agre et al., 2002) and likely play important roles in the waste internalization process. Based on our findings, we postulate that the functional significance of Aß may be structural stabilization of waste-internalizing structures and canals to prevent their collapse during the uptake process. We propose that tau protein may govern the quantitatively appropriate release of waste-internalizing structures. We postulate that AD-related Aβ-plaques and tau tangles likely show hypertrophic pathologies of this glial-canal-system and associated waste-internalizing receptacles.

DOI: https://doi.org/10.1101/2025.04.08.647836
Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2515113122

Amyloid β-dependent neuronal silencing through synaptic decoupling.

Yonghai Zhang, Hsing-Jung Chen-Engerer, Kuan Zhang, Benedikt Zott, Zsuzsanna Varga, Yang Chen, Xiaowei Chen, Hongbo Jia, Bert Sakmann, Israel Nelken, Arthur Konnerth.

  Amyloid β (Aβ)-dependent circuit dysfunction in Alzheimer's disease (AD) is determined by a puzzling mix of hyperactive and inactive ("silent") brain neurons. Recent studies identified excessive glutamate accumulation as a key Aβ-dependent determinant of hyperactivity. The cellular mechanisms underlying neuronal silence depend on both Aβ and tau protein pathologies, with an unknown role of Aβ. Here, by using single-cell-initiated rabies virus (RV) tracing in mouse models of β-amyloidosis, we demonstrate that the presynaptic connectivity of silent, but not that of hyperactive, neurons is severely disrupted. Furthermore, silent neurons display a major spine loss and strongly suppressed synaptic activity. Thus, we suggest that synaptic decoupling is an Aβ-dependent cellular mechanism underlying progressive neuronal silencing and a critical factor for the cognitive impairments encountered in AD.

Keywords:  Alzheimer’s disease; amyloid beta; neuronal dysfunction; synapse loss; two-photon imaging

DOI:  https://doi.org/10.1073/pnas.2515113122
FASEB J. 2025 Sep 15. 39(17): e70894

Deficiency of Microglial Hv1 Protects Against Lipopolysaccharide-Induced Neuroinflammation via the NF-κB Signaling Pathway and HIF1α-Mediated Metabolic Reprogramming.

Lingbin Sun, Xihua Wang, Shuyuan Guan, Ping Zhang, Dongling Chen, Tao Luo.

  Neuroinflammation plays a pivotal role in the initiation and progression of cognitive impairments. Hv1 channels have been implicated in proton extrusion, microglial activation, and neuroinflammation onset. Despite this, the specific mechanisms by which Hv1 deficiency mitigates neuroinflammation and its impact on pathophysiological processes are not fully understood. In this study, we investigated the role of Hv1 in LPS-induced hippocampal inflammation and cognitive deficits. Utilizing both knockout/knockdown and overexpression methodologies, we uncovered Hv1's contribution to neuroinflammatory processes. Our findings reveal that Hv1 loss exerts dual protective effects against LPS-induced neuroinflammation through NF-κB-mediated cytokine production and PI3K/Akt/HIF1α-mediated aerobic glycolysis, as evidenced by RNA sequencing and metabolomics analysis. Given the pivotal function of NF-κB in these responses, we observed a decrease in NF-κB activation and a reduction in the production of pro-inflammatory mediators in microglia with Hv1 deficiency. Conversely, the luciferase reporter assay and EMSA revealed that Hv1 overexpression augments NF-κB signaling. Furthermore, Hv1 deficiency resulted in reduced HIF1α expression and downregulation of its target genes, including HK2 and PFKFB3, thereby inhibiting aerobic glycolysis. In vivo results reveal a distinct microglial Hv1 role in regulating microglial metabolic reprogramming and neuroinflammation in cognitive deficits, suggesting Hv1 as a potential therapeutic target for neuroinflammation mediated by microglia, especially in the context of NF-κB dysregulation. Our findings highlight the significance of targeting aerobic glycolysis in the regulation of cognitive impairments. Additionally, our research provides novel insights into Hv1's regulatory influence on neuroinflammation via NF-κB signaling and metabolic reprogramming pathways.

Keywords:  Hv1; metabolic reprogramming; microglia; neuroinflammation

DOI:  https://doi.org/10.1096/fj.202402271RRR
Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01003-4. [Epub ahead of print]44(9): 116232

Emerging roles for innate and adaptive immunity in tauopathies.

Alexis M Johnson, John R Lukens.

  Tauopathies encompass a large majority of dementia diagnoses and are characterized by toxic neuronal or glial inclusions of the microtubule-associated protein tau. Tau has a high propensity to induce prion-like spreading throughout the brain via a variety of mechanisms, making tauopathy a rapid and lethal form of neurodegeneration that currently lacks an effective therapy or cure. Tau aggregation and neuronal loss associated with this pathology are accompanied by robust neuroinflammation. Innate immune responses-particularly those involving microglial activation, altered lipid metabolism, and type I interferon signaling-have emerged as key drivers of tau hyperphosphorylation and aggregation. Recent advances also point to a significant role for the adaptive immune system in shaping tauopathy progression. This review examines the current understanding of innate immunity in tauopathies and highlights emerging evidence linking T cell responses to tauopathy progression. Last, we conclude with a discussion of potential ways in which the immune system can be harnessed to treat tauopathy.

Keywords:  Alzheimer’s disease; CP: Immunology; CP: Neuroscience; T cells; adaptive immunity; disease-associated microglia; frontotemporal dementia; innate immunity; microglia; neurodegenerative disease; neuroimmunology; tauopathy

DOI:  https://doi.org/10.1016/j.celrep.2025.116232
Sci Adv. 2025 Aug 29. 11(35): eadw2464

STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome.

Virginia Andreani, Aaron James Forde, Manfred Fliegauf, Giulia Bressan, Vera Noé, Nils Ott, Shiva Saghafi, Larsen Vornholz, Sophie E Isay, Jürgen Ruland, Philipp Henneke, Bodo Grimbacher.

The autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency, which originates from heterozygous missense mutations in the signal transducer and activator of transcription 3 (STAT3) gene. It is accepted that most STAT3 variants causing AD-HIES are dominant negative. Whether haploinsufficient mutations cause a phenotype in humans is still debated. We report on a family with a heterozygous STAT3 nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a Stat3 haploinsufficient (Stat3+/-) mouse model in which we found that Stat3+/- mice had increased IgE serum levels, reduced TH17 cell differentiation, and were susceptible to a cutaneous Staphylococcus aureus infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in STAT3 with residual protein expression as an important cause for immune deficiency. The implications extend to the diagnosis of immunodeficiency disorders and to the design of gene therapy in situations where gene dosage matters.

DOI: https://doi.org/10.1126/sciadv.adw2464
Acta Neuropathol. 2025 Sep 04. 150(1): 24

Down syndrome and a presenilin 2 variant: dual genetic risk of Alzheimer's disease.

Jordan Ogg, Nadia Postupna, Laura E Gibbons, Jeanelle Ariza, Ming Xiao, Luciana M Fonseca, Suman Jayadev, C Dirk Keene, Thomas D Bird, Caitlin S Latimer.

  Early onset familial Alzheimer's disease (EOFAD) is rare compared to sporadic AD, but dominant variants in genes involved in amyloid β (Aβ) processing are well-described. One such variant is in the presenilin 2 (PSEN2) gene, N141I, and was first described in a family with Volga German descent. Separately, individuals with Down syndrome (DS) are also at risk for early onset AD, having an extra copy of an amyloid precursor protein gene. While either can drive EOFAD alone, it is extremely rare for both to occur within one individual. Here we describe a unique case of a 48-year-old individual, with both DS and the PSEN2 N141I variant. We investigated whether having two high-risk AD variants results in worsened or distinct pathology compared to single variant carriers. Neuropathologic evaluation, quantitative pathology, and spatial proteomic profiling (NanoString Geomx Digital Spatial Profiling) were performed on post-mortem tissue of the index case compared to individuals with DS and N141I variants alone. Analysis in the index case revealed increased total Aβ burden in multiple brain regions compared to the average levels observed in PSEN2 carriers and DS cases, but not for hyperphosphorylated tau or neuroinflammatory markers. Index case appeared to have more pronounced Aβ pathological burden than the PSEN2 subgroup and was more similar to the DS subgroup in several measurements: the Aβ burden, density of Aβ plaques, fibrillar and dense-core plaques, and the density of ionized calcium binding adaptor molecule 1 (Iba1) labelling in MSTG. As such, it appears that compounded genetic risk for AD was additive for Aβ burden, but not tau or neuroinflammation. This rare case offers new insight into how compounded risk may additively enhance amyloid pathology independently from tau. This underscores the importance of investigating synergistic and additive risk in neurodegenerative disease.

Keywords:  Alzheimer disease; Neuropathology; PSEN2 variant; Trisomy 21

DOI:  https://doi.org/10.1007/s00401-025-02931-1
FASEB J. 2025 Sep 15. 39(17): e71006

Dual Pro-Angiogenic and Pro-Fibrotic MARCO+ Microglial Phenotype in Diabetic Retinopathy.

Qinyuan Gu, Xiying Mao, Jingyi Xu, Pengfei Ge, Xinjing Wu, Chengkun Wang, Jingfan Wang, Hongying Li, Yuanyuan Fan, Tianhao Xiao, Qinghuai Liu, Ping Xie, Zizhong Hu.

  Proliferative diabetic retinopathy (PDR) is a complication of diabetic microangiopathy that can cause severe visual impairment. Due to retinal neovascularization and fibrovascular membrane (FVM) formation, inhibition of vascularization and fibrosis plays a key role in PDR. In our study, single-cell sequencing of FVMs from PDR patients identified a MARCO+ microglial subpopulation exhibiting both pro-angiogenic and pro-fibrotic effects. In vitro experiments demonstrated that glycated albumin (GA) significantly upregulated MARCO expression in BV2 cells in a dose-dependent manner. In vivo experiments, oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models were established in wild-type (WT) and MARCO-/- mice. The accumulation of MARCO+ microglia promoted retinal angiogenesis and fibrogenesis in WT mouse models, but not in MARCO-/- mouse models. Mechanistically, next-generation sequencing confirmed that the activation of the TLR4/NF-κB signaling pathway results in the increased expression of MARCO+ microglia. Furthermore, the targeted drug PolyG, which inhibits MARCO+ microglia, resulted in reduced angiogenesis and fibrogenesis in mouse models. Taken together, we demonstrate that MARCO+ microglia could be a potential therapeutic target for ocular angiogenic and fibrotic diseases.

Keywords:  MARCO protein; diabetic retinopathy; fibrosis; microglia; neovascularization

DOI:  https://doi.org/10.1096/fj.202502138R
Acta Neuropathol Commun. 2025 Sep 02. 13(1): 187

Identification and validation of a tear fluid-derived protein biomarker signature in patients with amyotrophic lateral sclerosis.

Lena-Sophie Scholl, Antonia F Demleitner, Jenny Riedel, Seren Adachi, Lisa Neuenroth, Clara Meijs, Laura Tzeplaeff, Lucas Caldi Gomes, Ana Galhoz, Isabell Cordts, Christof Lenz, Michael Menden, Paul Lingor.

  The diagnosis of Amyotrophic Lateral Sclerosis (ALS) remains challenging, particularly in early stages, where characteristic symptoms may be subtle and nonspecific. The development of disease-specific and clinically validated biomarkers is crucial to optimize diagnosis. Here, we explored tear fluid (TF) as a promising ALS biomarker source, given its accessibility, anatomical proximity to the brainstem as an important site of neurodegeneration, and proven discriminative power in other neurodegenerative diseases. Using a discovery approach, we profiled protein abundance in TF of ALS patients (n = 49) and controls (n = 54) via data-independent acquisition mass spectrometry. Biostatistical analysis and machine learning identified differential protein abundance and pathways in ALS, leading to a protein signature. These proteins were validated by Western blot in an independent cohort (ALS n = 51; controls n = 52), and their discriminatory performance was assessed in-silico employing machine learning. 876 proteins were consistently detected in TF, with 106 differentially abundant in ALS. A six-protein signature, including CRYM, PFKL, CAPZA2, ALDH16A1, SERPINC1, and HP, exhibited discriminatory potential. We replicated significant differences of SERPINC1 and HP levels between ALS and controls across the cohorts, and their combination yielded the best in-silico performance. Overall, this investigation of TF proteomics in ALS and controls revealed dysregulated proteins and pathways, highlighting inflammation as a key disease feature, strengthening the potential of TF as a source for biomarker discovery.

Keywords:  Amyotrophic lateral sclerosis; Biomarker; Diagnosis; Neurodegeneration; Proteomics; Tear fluid

DOI:  https://doi.org/10.1186/s40478-025-02109-6
Redox Biol. 2025 Aug 28. pii: S2213-2317(25)00364-7. [Epub ahead of print]86 103851

Enhancing microglial antioxidant capacity via the ascorbate transporter SVCT2 delays onset and modifies disease progression in mouse models of Alzheimer's disease.

Camila C Portugal, Evelyn C S Santos, Ana Monteiro-Pacheco, Sara Costa-Pinto, Tiago O Almeida, Joana Tedim-Moreira, Dora Gavin, Teresa Canedo, Fabiana Oliveira, Isabel Cardoso, Teresa Summavielle, Sandra H Vaz, Renato Socodato, João B Relvas.

  Despite clear evidence that vitamin C levels are depleted in the brains of Alzheimer's disease (AD) patients, dietary supplementation has consistently failed in clinical trials, suggesting a critical bottleneck not in systemic supply, but in its transport into brain cells. Here, we identify this bottleneck as a progressive downregulation of the ascorbate transporter, Slc23a2, also known as SVCT2, in microglia. Then we hypothesized that bypassing this cellular deficiency via targeted SVCT2 overexpression in microglia could either prevent the onset of pathology or rescue established functional deficits. Indeed, overexpressing SVCT2 in microglia before disease onset in 5xFAD mice triggered a profound redox reprogramming, resulting in a unique "hybrid" neuroprotective microglial phenotype that co-expressed both homeostatic and disease-associated markers. Functionally, this leads to decreased amyloid plaque burden and strengthens the synaptic bioenergetic capacity, which consequently prevents the development of synaptic and memory deficits. Strikingly, when employed after disease establishment, SVCT2 overexpression rescued synaptic plasticity and memory performance despite not affecting the existing amyloid burden. This rescue was driven by changes in the microglial secretory pathways. Collectively, these findings resolve a long-standing clinical paradox by establishing that neuroprotection depends not on systemic vitamin C intake but on the brain's cellular uptake machinery. This offers a mechanistic explanation for the failure of dietary supplementation in AD and identifies SVCT2 as a promising therapeutic target against the neurodegenerative process in AD.

Keywords:  5xFAD; APP/PS1; Ascorbate; LTP; Neurodegenerative diseases; Proteomics; RNA sequencing; SVCT2; Slc23a2

DOI:  https://doi.org/10.1016/j.redox.2025.103851
Sci Adv. 2025 Aug 29. 11(35): eadw0128

Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits.

Sofie Kessels, Chloë Trippaers, Melanie Mertens, Ibrahim Hamad, Ben Rombaut, Art Janssen, Keerthana Ramanathan, Sam Duwé, Adelaïde M Gharghani, Rune Theuwis, Amber Delbroek, Tim Vangansewinkel, Lisa Berden, Jolien Beeken, Patrick Vandormael, Suresh Poovathingal, Thomas Voets, Markus Kleinewietfeld, Laurent Nguyen, Jack P Antel, Luke M Healy, Sally A Cowley, Koko Ishizuka, Jean-Michel Rigo, Jelle Hendrix, Tim Vanmierlo, Ilse Dewachter, Yeranddy A Alpizar, Akira Sawa, Bert Brône.

Synaptic dysfunction is a hallmark of neurodevelopmental disorders (NDDs), often linked to genes involved in cytoskeletal regulation. While the role of these genes has been extensively studied in neurons, microglial functions such as phagocytosis are also dependent on cytoskeletal dynamics. We demonstrate that disturbance of actin cytoskeletal regulation in microglia, modeled by genetically impairing the scaffold protein Disrupted-in-Schizophrenia 1 (DISC1), which integrates actin-binding proteins, causes a shift in actin regulatory balance favoring filopodial versus lamellipodial actin organization. The resulting microglia-specific dysregulation of actin dynamics leads to excessive uptake of synaptic proteins. Genetically engineered DISC1-deficient mice show diminished hippocampal excitatory transmission and associated spatial memory deficits. Reintroducing wild-type microglia-like cells via bone marrow transplantation in adult DISC1-deficient mice restores the synaptic function of neurons and rescues cognitive performance. These findings reveal a pivotal role for microglial actin cytoskeletal remodeling in preserving synaptic integrity and cognitive health. Targeting microglial cytoskeletal dynamics may effectively address cognitive impairments associated with NDDs, even in adulthood.

DOI: https://doi.org/10.1126/sciadv.adw0128