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39 Publications visible to you, out of a total of 39
Injury-specific factors in the cerebrospinal fluid regulate astrocyte plasticity in the human brain.

Abstract (Expand)

The glial environment influences neurological disease progression, yet much of our knowledge still relies on preclinical animal studies, especially regarding astrocyte heterogeneity. In murine models … of traumatic brain injury, beneficial functions of proliferating reactive astrocytes on disease outcome have been unraveled, but little is known regarding if and when they are present in human brain pathology. Here we examined a broad spectrum of pathologies with and without intracerebral hemorrhage and found a striking correlation between lesions involving blood-brain barrier rupture and astrocyte proliferation that was further corroborated in an assay probing for neural stem cell potential. Most importantly, proteomic analysis unraveled a crucial signaling pathway regulating this astrocyte plasticity with GALECTIN3 as a novel marker for proliferating astrocytes and the GALECTIN3-binding protein LGALS3BP as a functional hub mediating astrocyte proliferation and neurosphere formation. Taken together, this work identifies a therapeutically relevant astrocyte response and their molecular regulators in different pathologies affecting the human cerebral cortex.

Authors: Swetlana Sirko, Christian Schichor, Patrizia Della Vecchia, Fabian Metzger, Giovanna Sonsalla, Tatiana Simon, Martina Bürkle, Sofia Kalpazidou, Jovica Ninkovic, Giacomo Masserdotti, Jean-Frederic Sauniere, Valentina Iacobelli, Stefano Iacobelli, Claire Delbridge, Stefanie M Hauck, Jörg-Christian Tonn, Magdalena Götz

Date Published: 8th Dec 2023

Publication Type: Journal

High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Abstract (Expand)

Oxytocin-expressing paraventricular hypothalamic neurons (PVN<sup>OT</sup> neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy … homeostasis. However, the molecular underpinnings by which PVN<sup>OT</sup> neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVN<sup>OT</sup> neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVN<sup>OT</sup> neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVN<sup>OT</sup> neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVN<sup>OT</sup> signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Authors: Tim Gruber, Franziska Lechner, Cahuê Murat, Raian E Contreras, Eva Sanchez-Quant, Viktorian Miok, Konstantinos Makris, Ophélia Le Thuc, Ismael González-García, Elena García-Clave, Ferdinand Althammer, Quirin Krabichler, Lisa M DeCamp, Russell G Jones, Dominik Lutter, Rhiannan H Williams, Paul T Pfluger, Timo D Müller, Stephen C Woods, John Andrew Pospisilik, Celia P Martinez-Jimenez, Matthias H Tschöp, Valery Grinevich, Cristina Garcia-Caceres

Date Published: 31st Oct 2023

Publication Type: Journal

Distinct molecular profiles of skull bone marrow in health and neurological disorders.

Abstract (Expand)

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that … the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.

Authors: Zeynep Ilgin Kolabas, Louis B Kuemmerle, Robert Perneczky, Benjamin Förstera, Selin Ulukaya, Mayar Ali, Saketh Kapoor, Laura M Bartos, Maren Büttner, Ozum Sehnaz Caliskan, Zhouyi Rong, Hongcheng Mai, Luciano Höher, Denise Jeridi, Muge Molbay, Igor Khalin, Ioannis K Deligiannis, Moritz Negwer, Kenny Roberts, Alba Simats, Olga Carofiglio, Mihail I Todorov, Izabela Horvath, Furkan Ozturk, Selina Hummel, Gloria Biechele, Artem Zatcepin, Marcus Unterrainer, Johannes Gnörich, Jay Roodselaar, Joshua Shrouder, Pardis Khosravani, Benjamin Tast, Lisa Richter, Laura Díaz-Marugán, Doris Kaltenecker, Laurin Lux, Ying Chen, Shan Zhao, Boris-Stephan Rauchmann, Michael Sterr, Ines Kunze, Karen Stanic, Vanessa W Y Kan, Simon Besson-Girard, Sabrina Katzdobler, Carla Palleis, Julia Schädler, Johannes C Paetzold, Sabine Liebscher, Anja E Hauser, Özgün Gökçe, Heiko Lickert, Hanno Steinke, Corinne Benakis, Christian Braun, Celia P Martinez-Jimenez, Katharina Buerger, Nathalie L Albert, Günter Höglinger, Johannes Levin, Christian Haass, Anna Kopczak, Martin Dichgans, Joachim Havla, Tania Kümpfel, Martin Kerschensteiner, Martina Schifferer, Mikael Simons, Arthur Liesz, Natalie Krahmer, Omer A Bayraktar, Nicolai Franzmeier, Nikolaus Plesnila, Suheda Erener, Victor G Puelles, Claire Delbridge, Harsharan Singh Bhatia, Farida Hellal, Markus Elsner, Ingo Bechmann, Benjamin Ondruschka, Matthias Brendel, Fabian J Theis, Ali Ertürk

Date Published: 17th Aug 2023

Publication Type: Journal

Met/HGFR triggers detrimental reactive microglia in TBI.

Abstract (Expand)

The complexity of signaling events and cellular responses unfolding in neuronal, glial, and immune cells upon traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links … and targets for intervention. We use array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then scrutinize the large-scale effects of perturbation of Met/HGFR, VEGFR1, and Btk signaling by small molecules. We show Met/HGFR as a selective modifier of early microglial response and that Met/HGFR blockade prevents the induction of microglial inflammatory mediators, of reactive microglia morphology, and TBI-associated responses in neurons and vasculature. Both acute and prolonged Met/HGFR inhibition ameliorate neuronal survival and motor recovery. Early elevation of HGF itself in the cerebrospinal fluid of TBI patients suggests that this mechanism has translational value in human subjects. Our findings identify Met/HGFR as a modulator of early neuroinflammation in TBI with promising translational potential.

Authors: Rida Rehman, Michael Miller, Sruthi Sankari Krishnamurthy, Jacob Kjell, Lobna Elsayed, Stefanie M Hauck, Florian Olde Heuvel, Alison Conquest, Akila Chandrasekar, Albert Ludolph, Tobias Boeckers, Medhanie A Mulaw, Maria Cristina Morganti-Kossmann, Aya Takeoka, Francesco Roselli, Magdalena Götz

Date Published: 27th Dec 2022

Publication Type: Journal

Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease.

Abstract (Expand)

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate … how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

Authors: Alexa Pichet Binette, Nicolai Franzmeier, Nicola Spotorno, Michael Ewers, Matthias Brendel, Davina Biel, Olof Strandberg, Shorena Janelidze, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Ruben Smith, Erik Stomrud, Rik Ossenkoppele, Oskar Hansson

Date Published: 4th Nov 2022

Publication Type: Journal

IKKβ binds NLRP3 providing a shortcut to inflammasome activation for rapid immune responses.

Abstract

Not specified

Authors: Yaw Asare, Margarita Shnipova, Luka Živković, Christina Schlegl, Federica Tosato, Arailym Aronova, Markus Brandhofer, Laura Strohm, Nathalie Beaufort, Rainer Malik, Christian Weber, Jürgen Bernhagen, Martin Dichgans

Date Published: 19th Oct 2022

Publication Type: Journal

Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner.

Abstract (Expand)

Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of … the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecular responses following exposure to a high-fat high-sugar (HFHS) diet, specifically in the ARC. Using RNA sequencing and proteomics, we showed that astrocytes have a distinct transcriptomic and proteomic profile dependent on their anatomical location, with a major proteomic reprogramming in hypothalamic astrocytes. By ARC single-cell sequencing, we observed that a HFHS diet dictates time- and cell- specific transcriptomic responses, revealing that astrocytes have the most distinct regulatory pattern compared to other cell types. Lastly, we topographically and molecularly characterized astrocytes expressing glial fibrillary acidic protein and/or aldehyde dehydrogenase 1 family member L1 in the ARC, of which the abundance was significantly increased, as well as the alteration in their spatial and molecular profiles, with a HFHS diet. Together, our results provide a detailed multi-omics view on the spatial and temporal changes of astrocytes particularly in the ARC during different time points of adaptation to a high calorie diet.

Authors: Luiza Maria Lutomska, Viktorian Miok, Natalie Krahmer, Ismael González García, Tim Gruber, Ophélia Le Thuc, Cahuê Db Murat, Beata Legutko, Michael Sterr, Gesine Saher, Heiko Lickert, Timo D Müller, Siegfried Ussar, Matthias H Tschöp, Dominik Lutter, Cristina Garcia-Caceres

Date Published: 8th Jul 2022

Publication Type: Journal

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