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91 Publications visible to you, out of a total of 91
T cells modulate the microglial response to brain ischemia.

Abstract (Expand)

Neuroinflammation after stroke is characterized by the activation of resident microglia and the invasion of circulating leukocytes into the brain. Although lymphocytes infiltrate the brain in small … number, they have been consistently demonstrated to be the most potent leukocyte subpopulation contributing to secondary inflammatory brain injury. However, the exact mechanism of how this minimal number of lymphocytes can profoundly affect stroke outcome is still largely elusive. Here, using a mouse model for ischemic stroke, we demonstrated that early activation of microglia in response to stroke is differentially regulated by distinct T cell subpopulations - with T(H1) cells inducing a type I INF signaling in microglia and regulatory T cells (T(REG)) cells promoting microglial genes associated with chemotaxis. Acute treatment with engineered T cells overexpressing IL-10 administered into the cisterna magna after stroke induces a switch of microglial gene expression to a profile associated with pro-regenerative functions. Whereas microglia polarization by T cell subsets did not affect the acute development of the infarct volume, these findings substantiate the role of T cells in stroke by polarizing the microglial phenotype. Targeting T cell-microglia interactions can have direct translational relevance for further development of immune-targeted therapies for stroke and other neuroinflammatory conditions.

Authors: C. Benakis, A. Simats, S. Tritschler, S. Heindl, S. Besson-Girard, G. Llovera, K. Pinkham, A. Kolz, A. Ricci, F. J. Theis, S. Bittner, O. Gokce, A. Peters, A. Liesz

Date Published: 13th Dec 2022

Publication Type: Journal

Lipid and protein content profiling of isolated native autophagic vesicles.

Abstract (Expand)

Autophagy is responsible for clearance of an extensive portfolio of cargoes, which are sequestered into vesicles, called autophagosomes, and are delivered to lysosomes for degradation. The pathway is … highly dynamic and responsive to several stress conditions. However, the phospholipid composition and protein contents of human autophagosomes under changing autophagy rates are elusive so far. Here, we introduce an antibody-based FACS-mediated approach for the isolation of native autophagic vesicles and ensured the quality of the preparations. Employing quantitative lipidomics, we analyze phospholipids present within human autophagic vesicles purified upon basal autophagy, starvation, and proteasome inhibition. Importantly, besides phosphoglycerides, we identify sphingomyelin within autophagic vesicles and show that the phospholipid composition is unaffected by the different conditions. Employing quantitative proteomics, we obtain cargo profiles of autophagic vesicles isolated upon the different treatment paradigms. Interestingly, starvation shows only subtle effects, while proteasome inhibition results in the enhanced presence of ubiquitin-proteasome pathway factors within autophagic vesicles. Thus, here we present a powerful method for the isolation of native autophagic vesicles, which enabled profound phospholipid and cargo analyses.

Authors: D. Schmitt, S. Bozkurt, P. Henning-Domres, H. Huesmann, S. Eimer, L. Bindila, C. Behrends, E. Boyle, F. Wilfling, G. Tascher, C. Munch, C. Behl, A. Kern

Date Published: 6th Dec 2022

Publication Type: Journal

Experimental evidence for temporal uncoupling of brain Abeta deposition and neurodegenerative sequelae.

Abstract (Expand)

Brain Abeta deposition is a key early event in the pathogenesis of Alzheimer s disease (AD), but the long presymptomatic phase and poor correlation between Abeta deposition and clinical symptoms remain … puzzling. To elucidate the dependency of downstream pathologies on Abeta, we analyzed the trajectories of cerebral Abeta accumulation, Abeta seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Abeta-precursor protein transgenic mice. We find that Abeta deposition increases linearly until it reaches an apparent plateau at a late age, while Abeta seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Abeta generation in amyloid-laden mice reduced Abeta deposition and associated glial changes, but failed to reduce Abeta seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Abeta generation was started at pre-amyloid stages, CSF NfL did not increase despite some Abeta deposition, microglial activation, and robust brain Abeta seeding activity. A dissociation of Abeta load and CSF NfL trajectories was also found in familial AD, consistent with the view that Abeta aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Abeta seeding activity is saturated and before Abeta deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.

Authors: C. Rother, R. E. Uhlmann, S. A. Muller, J. Schelle, A. Skodras, U. Obermuller, L. M. Hasler, M. Lambert, F. Baumann, Y. Xu, C. Bergmann, G. Salvadori, M. Loos, I. Brzak, D. Shimshek, U. Neumann, L. C. Walker, S. A. Schultz, J. P. Chhatwal, S. A. Kaeser, S. F. Lichtenthaler, M. Staufenbiel, M. Jucker

Date Published: 28th Nov 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

CD8(+) T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging.

Abstract (Expand)

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related … alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8(+) T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8(+) T cells in aging white matter. In summary, we provide evidence that CD8(+) T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

Authors: T. Kaya, N. Mattugini, L. Liu, H. Ji, L. Cantuti-Castelvetri, J. Wu, M. Schifferer, J. Groh, R. Martini, S. Besson-Girard, S. Kaji, A. Liesz, O. Gokce, M. Simons

Date Published: 26th Oct 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

ALS-linked loss of Cyclin-F function affects HSP90.

Abstract (Expand)

The founding member of the F-box protein family, Cyclin-F, serves as a substrate adaptor for the E3 ligase Skp1-Cul1-F-box (SCF)<sup>Cyclin-F</sup> which is responsible for … ubiquitination of proteins involved in cell cycle progression, DNA damage and mitotic fidelity. Missense mutations in <i>CCNF</i> encoding for Cyclin-F are associated with amyotrophic lateral sclerosis (ALS). However, it remains elusive whether <i>CCNF</i> mutations affect the substrate adaptor function of Cyclin-F and whether altered SCF<sup>Cyclin-F</sup>-mediated ubiquitination contributes to pathogenesis in <i>CCNF</i> mutation carriers. To address these questions, we set out to identify new SCF<sup>Cyclin-F</sup> targets in neuronal and ALS patient-derived cells. Mass spectrometry-based ubiquitinome profiling of <i>CCNF</i> knockout and mutant cell lines as well as Cyclin-F proximity and interaction proteomics converged on the HSP90 chaperone machinery as new substrate candidate. Biochemical analyses provided evidence for a Cyclin-F-dependent association and ubiquitination of HSP90AB1 and implied a regulatory role that could affect the binding of a number of HSP90 clients and co-factors. Together, our results point to a possible Cyclin-F loss-of-function-mediated chaperone dysregulation that might be relevant for ALS.

Authors: A. Siebert, V. Gattringer, J. H. Weishaupt, C. Behrends

Date Published: 16th Sep 2022

Publication Type: Journal

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