bims-micgli 2026-02-01 papers

bims-micgli

Biomed News

on Microglia

Issue of 2026–02–01
eight papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.
Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease.
Spatially resolved molecular signatures of Lewy body dementia.
The glymphatic system clears amyloid beta and tau from brain to plasma in humans.
From Neuron-Centric to Glia-Centric: How Aging Glial Networks Drive Neurodegenerative Disease.
Evaluation of ASC as a therapeutic target for Alzheimer's disease.
Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutières syndrome neuropathology.
Clonal CD8+ T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.

Nat Commun. 2026 Jan 24.

TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.

Astrid F Feiten, Kilian Dahm, Kai Schlepckow, Bettina van Lengerich, Jung H Suh, Anika Reifschneider, Benedikt Wefers, Laura M Bartos, Karin Wind-Mark, Lis de Weerd, Thomas Ulas, Elena De-Domenico, Pia Grundschöttel, Stefan Paulusch, Benjamin Tast, Tamisa Honda, Stephan A Müller, Matthias Becker, Igor Khalin, Alessio Ricci, Arthur Liesz, Bettina Brunner, Claudia Krenner, Katrin Buschmann, Brigitte Nuscher, Lena Spieth, Niklas Junker, Stefan A Berghoff, Sonnet S Davis, Jonas J Neher, Wolfgang Wurst, Nikolaus Plesnila, Joseph W Lewcock, Mikael Simons, Stefan F Lichtenthaler, Gilbert Di Paolo, Matthias Brendel, Anja Capell, Kathryn M Monroe, Joachim L Schultze, Christian Haass.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists.

DOI: https://doi.org/10.1038/s41467-026-68706-8
Annu Rev Pathol. 2026 Jan;21(1): 59-80

Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease.

Jordan E McKinney, Mariko L Bennett, F Chris Bennett.

  Microglia-the parenchymal tissue-resident macrophages of the brain and spinal cord-are essential to support brain health by integrating environmental cues and performing immune functions and reparative processes. Yet across neurodegenerative diseases, these long-lived cells become increasingly unable to meet the demands of their homeostatic roles. In this review, we trace the arc of microglial function from competence to dysfunction, examining how their roles, for example, in synaptic pruning, phagocytosis, and interferon signaling, can shift from protective to pathogenic. Using Alzheimer's disease, inherited microgliopathies, and Aicardi-Goutières syndrome as case studies, we highlight the ways in which microglia fail-through metabolic exhaustion, lysosomal overload, inflammatory gain of function, or failure to respond. We consider how genetic and environmental factors converge to drive this "microglial incompetence," and discuss emerging strategies to reset or replace dysfunctional microglia. Understanding when and how microglia go awry may unlock new paths for treating a wide spectrum of neurodegenerative diseases.

Keywords:  Alzheimer's disease; interferonopathy; microglia; microglia replacement; microgliopathies; neurodegeneration

DOI:  https://doi.org/10.1146/annurev-pathmechdis-042624-114332
Acta Neuropathol. 2026 Jan 26. 151(1): 10

Spatially resolved molecular signatures of Lewy body dementia.

Yunjung Jin, Kai Chen, Alexander Q Wixom, Zonghua Li, Shunsuke Koga, Hiroaki Sekiya, Gisela Xhafkollari, Monica Castanedes-Casey, Hannah Santhakumar, Axel D Meneses, Abigail J Neff, Guojun Bu, Michael G Heckman, Yuanhang Liu, Owen A Ross, Dennis W Dickson, Na Zhao.

  Lewy body dementia (LBD), encompassing dementia with Lewy bodies and Parkinson's disease dementia, is neuropathologically defined by neuronal accumulation of α-synuclein encoded by the SNCA gene. Genetic risk factors strongly influence LBD susceptibility, including SNCA multiplication, particularly triplication, and the apolipoprotein E ε4 allele (APOE4), the strongest common genetic risk factor for LBD. While SNCA is predominantly expressed in neurons and APOE primarily in glial cells, how these genetic factors converge to impact neuronal vulnerability and regional pathology in the human brain remains poorly understood. Here, we applied spatial transcriptomics to postmortem temporal cortex tissue from LBD cases with SNCA triplication or different APOE genotypes, alongside age- and sex-matched controls, to map gene expression within intact cortical architecture. We identified layer 5 of the gray matter as a particularly vulnerable region, characterized by elevated SNCA expression, pronounced synaptic and metabolic dysregulation, and exacerbation of these alterations in APOE4 carriers. Reelin signaling emerged as a core Lewy body-associated pathway disrupted across cortical layers, validated in independent postmortem cohorts and human-induced pluripotent stem cell (iPSC)-derived cortical organoids. In contrast, white matter exhibited distinct molecular alterations, including disrupted myelination pathways, with APOE4 carriers showing increased myelin debris and glial responses compared with non-carriers. Cell-type deconvolution informed by single-nucleus RNA sequencing further revealed APOE4-associated impairments in neuronal vulnerability and intercellular communication. Together, these findings define spatially and cell-type-specific mechanisms through which SNCA dosage and APOE4 genotype impact LBD pathology, providing insight into regionally distinct disease processes and potential targets for genetically stratified therapeutic interventions.

Keywords:   APOE ; SNCA ; Lewy body dementia; Reelin; Spatial transcriptomics

DOI:  https://doi.org/10.1007/s00401-026-02981-z
Nat Commun. 2026 Jan 27. 17(1): 715

The glymphatic system clears amyloid beta and tau from brain to plasma in humans.

Paul Dagum, Donald L Elbert, Laurent Giovangrandi, Tarandeep Singh, Venky V Venkatesh, Alejandro Corbellini, Robert M Kaplan, Swati Rane Levendovszky, Elizabeth Ludington, Kevin Yarasheski, Jeffrey Lowenkron, Carla VandeWeerd, Miranda M Lim, Jeffrey J Iliff.

Dysfunction of the glymphatic system has been proposed as a mechanistic link between sleep disruption and Alzheimer's disease (AD). In animal models, glymphatic impairment alone can drive AD pathology. Whether this system clears amyloid beta (Aβ) and tau in humans remains unknown. In a randomized crossover trial with 39 participants, we found that glymphatic clearance during normal sleep increased morning plasma levels of AD biomarkers compared to sleep deprivation. Participants underwent overnight monitoring using an investigational device that measured dynamic changes in synaptic-metabolic release and glymphatic activity. The observed changes mirrored predictions from a multicompartment model based on published data on Aβ and tau release and clearance. Our findings indicate that sleep-active physiological processes, particularly reduced brain parenchymal resistance, enhance overnight glymphatic clearance of AD biomarkers to plasma. These results support a key role for glymphatic function in AD pathophysiology and suggest its enhancement as a potential therapeutic strategy to slow disease progression.

DOI: https://doi.org/10.1038/s41467-026-68374-8
J Neurochem. 2026 Jan;170(1): e70361

From Neuron-Centric to Glia-Centric: How Aging Glial Networks Drive Neurodegenerative Disease.

Lívia de Sá Hayashide, Bruna Pessoa, Gustavo Dias, Bruno Pontes, Rafael Serafim Pinto, Luan Pereira Diniz.

  The traditional neuron-centric view of neurodegeneration is being replaced by a glial network-based framework. This shift recognizes that age-related dysfunction in non-neuronal cells critically shapes neuronal vulnerability and circuit resilience. Aging, the major risk factor for neurodegenerative diseases, is increasingly associated with the accumulation of senescent glial cells, particularly astrocytes, which emerge as early and active drivers of central nervous system decline. This review highlights astrocytic senescence as a key mechanism linking brain aging to neurodegeneration. Senescent astrocytes exhibit hallmark features including stable cell cycle arrest, mitochondrial dysfunction, and the acquisition of a senescence-associated secretory phenotype (SASP), which disrupts synaptic integrity, impairs proteostasis, and sustains chronic neuroinflammation. These alterations often precede overt neuronal loss in disorders such as Alzheimer's and Parkinson's disease. We discuss core hallmarks and biomarkers of glial senescence, emphasizing integrative strategies combining functional assays and molecular markers. We further highlight circulating SASP-related factors and extracellular vesicles as translational indicators of systemic senescence. Finally, we examine emerging senotherapeutic approaches aimed at restoring glial homeostasis, including senolytics, senomorphics, and CAR-T-based immunotherapies. Targeting glial senescence and interglial communication therefore represents a promising, though complex, paradigm-shifting avenue for delaying brain aging and mitigating neurodegenerative progression.

Keywords:  Senotherapy; astrocytes; brain aging; glial senescence; neurodegeneration; senescence‐associated secretory phenotype

DOI:  https://doi.org/10.1111/jnc.70361
Alzheimers Dement. 2026 Jan;22(1): e71104

Evaluation of ASC as a therapeutic target for Alzheimer's disease.

W Brent Clayton, Joshua A Kulas, Jiahui Liu, Nidhi Walia, Claudia Rangel-Barajas, Travis Johnson, Jie Zhang, Kun Huang, Andrew D Mesecar, Jeffrey L Dage, Bruce T Lamb, Alan D Palkowitz, Timothy I Richardson.

  Neuroinflammation is increasingly recognized as a central contributor to the pathogenesis and progression of Alzheimer's disease (AD). The apoptosis-associated speck-like protein containing a CARD (ASC), encoded by the PYCARD gene, plays a critical role in the formation of multiple inflammasomes, including NLRP3, a key mediator of inflammation signaling. Beyond its role in inflammasome formation, extracellular ASC specks have been shown to promote amyloid-β aggregation, showing a potential link between inflammation and plaque formation. In this review, we examine the role of ASC in AD pathology and highlight emerging tools to study ASC biology and strategies for ASC targeted drug discovery.

Keywords:  ASC; Alzheimer's disease; PYCARD; cell assays; drug discovery

DOI:  https://doi.org/10.1002/alz.71104
Elife. 2026 Jan 27. pii: RP102900. [Epub ahead of print]14

Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutières syndrome neuropathology.

Kelsey M Nemec, Genevieve Uy, V Sai Chaluvadi, Freddy S Purnell, Bilal Elfayoumi, Leila Byerly, Micaela L O'Reilly, Carleigh A O'Brien, William H Aisenberg, Sonia I Lombroso, Xinfeng Guo, Niklas Blank, Chet Huan Oon, Fazeela Yaqoob, Brian Temsamrit, Priyanka Rawat, Christoph A Thaiss, Will Bailis, Adam P Williamson, Qingde Wang, Mariko L Bennett, F Chris Bennett.

  Microglia, the brain's resident macrophages, can be reconstituted by surrogate cells - a process termed 'microglia replacement'. To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system's power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutières syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.

Keywords:  immunology; inflammation; leukodystrophies; microglia; microglia replacement; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.102900
Nat Immunol. 2026 Jan 27.

Clonal CD8+ T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.

Ryan Hobson, Samuel H S Levy, Chitra Mohinder Singh Singal, Delaney Flaherty, Harrison Xiao, Benjamin Ciener, Hasini Reddy, Nick Zabinyakov, Christine Y Kim, Andrew F Teich, Neil A Shneider, Elizabeth M Bradshaw, Wassim Elyaman.

Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.

DOI: https://doi.org/10.1038/s41590-025-02401-6