Publications

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35 Publications visible to you, out of a total of 35
A scalable human-zebrafish xenotransplantation model reveals gastrosome-mediated processing of dying neurons by human microglia

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Abstract Microglia engulf dying neurons through efferocytosis, a critical function in both development and disease. How microglia process the engulfed neuronal material—especially lipids—remains poorly …terial—especially lipids—remains poorly understood, despite its central role in neurodegeneration. Thus, we developed HuZIBRA, a scalable in vivo xenotransplantation model in which human iPSC-derived microglia-like cells (iMGLs) are introduced into the developing zebrafish brain (zf-hiMG), a system characterized by high levels of neuronal cell death and amenable to precise genetic and pharmacological manipulation. We show that human microglia-like cells recognize and engulf apoptotic zebrafish neurons, indicating conserved efferocytic mechanisms. In these cells, engulfed neuronal material accumulates into a distinct, lipid-rich intracellular compartment, the gastrosome, which we also observed in iMGLs placed in a human brain-like environment. The size of the human gastrosome dynamically reflects neuronal cell death levels and is regulated by key genes, including TREM2 and SLC37A2 . Pharmacological inhibition of the cholesterol transporter NPC1 induces gastrosome expansion and lipid accumulation, recapitulating pathological features of Niemann-Pick disease type C. Thus, HuZIBRA provides a powerful in vivo platform to uncover cell-autonomous adaptive responses of human microglia to apoptotic and metabolic stress, with the gastrosome emerging as a key integrator of neuronal debris processing and disease-relevant lipid metabolism.

Authors: Ambra Villani, Jana Wittmann, Tamara Wyss, Izaskun Mallona, Irene Santisteban Ortiz, Nathalie Tichy, Corinna Maria Biermeier, Monique Pena, Ayush Aditya Pal, Darren Gilmour, Simon T. Schafer, Francesca Peri

Date Published: 9th Apr 2026

Publication Type: Journal Article

A transcriptomic microglia taxonomy across mouse and human pathologies

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Abstract Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states … microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and pathological conditions. This atlas enables us to establish a comprehensive taxonomy of myeloid cell states across brain disorders and related mouse models, comprising 27 superclusters and 192 clusters that are prevalent across diseases and largely conserved. We augment this taxonomic framework with spatial transcriptomics to map how immune cell states are organized within tissue and interact with their local cellular environment. Using in vivo perturbations, we also show that activation-associated microglial states are dependent on interferon and colony-stimulating factor 1 receptor signaling. Together, these findings provide a spatially aware taxonomic framework for central nervous system immune cells in health and disease.

Authors: Chintan Chhatbar, Roman Sankowski, Michael Schulz, Takashi Shimizu, Marius Schwabenland, Ori Staszewski, Christian Scheiwe, Stefan Nessler, Katharina Borst, Anaelle Aurelie Dumas, Ella Trost, Daniel Berchtold, Wesley Brandão, Omar Mossad, Adrià Dalmau Gasull, Maximilian Frosch, Daniel Erny, Martin Diebold, Elena Guffart, Katharina Ternka, Mihaela Guranda, Janaki Manoja Vinnakota, Marina Friesen, Koliane Ouk, Inken Waltl, Michael LaMorte, Timothy R. Hammond, Giovanni Di Liberto, Ilena Vincenti, Mario Kreutzfeldt, Ibrahim T. Mughrabi, Yousef Al-Abed, Thomas Blank, Melanie Meyer-Luehmann, Yanick J. Crow, Nellwyn Hagen, Dimitry Ofengeim, Robert Zeiser, Matthias Kettwig, Jutta Gärtner, Andreas Meisel, Martin Schwemmle, Ulrich Kalinke, Jürgen Beck, Bertram Bengsch, Robert Thimme, Oleg Butovsky, Tamara Seredenina, Richard M. Ransohoff, Francisco J. Quintana, Katrin Kierdorf, Doron Merkler, Christine Stadelmann, Josef Priller, Marco Prinz

Date Published: 25th Mar 2026

Publication Type: Journal Article

Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis

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Abstract Chitinases are hydrolytic enzymes responsible for degrading chitin and have been evolutionarily conserved across various species. Although their signaling pathways are not fully understood, … fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1), and human-specific Chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS). ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of etiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1, and CHI3L2 levels are elevated in the cerebrospinal fluid (CSF) of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the chitinases’ role in ALS disease burden remain: namely, 1) which cell types in the central nervous system (CNS) are chitinase sources under physiological conditions, 2) which of these display chitinase upregulation in ALS, and 3) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize pre-clinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS vs. non-ALS controls, while CHI3L1 was more closely associated with inflammation and aging across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins as biomarkers, we propose that appreciating their expression patterns can aid in optimizing biomarker-guided trial design. Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.

Authors: Nayana Gaur, Christin Angerer, Zeynep I Gunes, Mihai Ancau, Mengzhe Wang, Henrick Riemenschneider, Charlene-Annett Hurler, Simon Mungwa, Patrick Lüningschrör, Anxhela Zhiti, Robert Steinbach, Michael Briese, Mugdha Srivastava, Mario Plaas, Andreas Hermann, Michael Sendtner, Sarah Jäkel, Dieter Edbauer, Jochen Herms, Sabine Liebscher, Julian Grosskreutz, Monika S Brill

Date Published: 28th Feb 2026

Publication Type: Journal Article

Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions

Abstract

Not specified

Authors: Ruoqing Feng, Lena Spieth, Lu Liu, Stefan Berghoff, Jonas Franz, Qian Liu, Zhen Wang, Vini Tiwari, Simona Vitale, Simon Frerich, Sergi Florensa, Niklas Junker, Ludwig Huber, Marco Keller, Christoph Müller, Franz Bracher, Xiaoke Ge, Patrick C.N. Rensen, Gijs Kooij, Leon Hosang, Serhii Chornyi, Martin Dichgans, Ozgun Gokce, Gesine Saher, Christine Stadelmann, Martin Giera, Janos Groh, Mikael Simons

Date Published: 1st Dec 2025

Publication Type: Journal Article

Microglia–neuron crosstalk through Hex–GM2–MGL2 maintains brain homeostasis

Abstract (Expand)

Abstract As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations 1 . They primarily interact with …ions 1 . They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses 2 . Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb , encoding the β subunit of β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner 3 . In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N -acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia–neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.

Authors: Maximilian Frosch, Takashi Shimizu, Emile Wogram, Lukas Amann, Lars Gruber, Ayelén I. Groisman, Maximilian Fliegauf, Marius Schwabenland, Chintan Chhatbar, Sabrina Zechel, Hendrik Rosewich, Jutta Gärtner, Francisco J. Quintana, Joerg M. Buescher, Thomas Blank, Harald Binder, Christine Stadelmann, Johannes J. Letzkus, Carsten Hopf, Takahiro Masuda, Klaus-Peter Knobeloch, Marco Prinz

Date Published: 6th Aug 2025

Publication Type: Journal Article

Brain-wide microstrokes affect the stability of memory circuits in the hippocampus

Abstract (Expand)

Abstract Cognitive deficits affect over 70% of stroke survivors, yet the mechanisms by which multiple small ischemic events contribute to cognitive decline remain poorly understood. In this study, we … In this study, we employed chronic two-photon calcium imaging to longitudinally track the fate of individual neurons in the hippocampus of mice navigating a virtual reality environment, both before and after inducing brain-wide microstrokes. Our findings reveal that, under normal conditions, hippocampal neurons exhibit varying degrees of stability in their spatial memory coding. However, microstrokes disrupted this functional network architecture, leading to cognitive impairments. Notably, the preservation of stable coding place cells, along with the stability, precision, and persistence of the hippocampal network, was strongly predictive of cognitive outcomes. Mice with more synchronously active place cells near important locations demonstrated recovery from cognitive impairment. This study uncovers critical cellular responses and network alterations following brain injury, providing a foundation for novel therapeutic strategies preventing cognitive decline.

Authors: Hendrik Heiser, Filippo Kiessler, Adrian Roggenbach, Victor Ibanez, Martin Wieckhorst, Fritjof Helmchen, Julijana Gjorgjieva, Anna-Sophia Wahl

Date Published: 11th Apr 2025

Publication Type: Journal Article

Repetitive concussions promote microglia-mediated engulfment of presynaptic excitatory input associated with cognitive dysfunction

Abstract (Expand)

Abstract Concussions are a current health concern and account for the vast majority of head trauma. While symptoms after a single impact are usually transient, repetitive concussions, as often occur …ften occur in sports, are responsible for persistent acute and chronic deficits. Here, we used a model of bilateral midline-centered concussions in mice to show that repetitive concussions selectively induce impairments in learning ability compared to single-impact injuries. Since microglial cells and their activation are considered key factors in degenerative pathology after brain trauma, we examined their structure and function after single and repetitive concussions in the cortex underlying the concussions and in the hippocampus. We found that only repetitive concussions led to a significant long-lasting structural activation of microglia and an increase in microglia-mediated engulfment of presynaptic excitatory synapses, while the elimination of inhibitory synapses was not altered. Since the density of excitatory input did not change during the 6-week study period, we hypothesize that there is a turnover of excitatory synapses following repetitive concussion that can be compensated for, anatomically but not behaviorally.

Authors: Maryam Chahin, Julius Mutschler, Stephanie P. Dzhuleva, Clara Dieterle, Leidy Reyes Jimenez, Srijan Raj Bhattarai, Valerie Van Steenbergen, Florence M. Bareyre

Date Published: 28th Feb 2025

Publication Type: Journal Article

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