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24 Publications visible to you, out of a total of 24
The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.

Abstract (Expand)

The beta-secretase BACE1 is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological … BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, non-human primates and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for a safer prevention of Alzheimer's disease.

Authors: A. Schmidt, B. Hrupka, F. van Bebber, S. Sunil Kumar, X. Feng, S. K. Tschirner, M. Assfalg, S. A. Muller, L. S. Hilger, L. I. Hofmann, M. Pigoni, G. Jocher, I. Voytyuk, E. L. Self, M. Ito, K. Hyakkoku, A. Yoshimura, N. Horiguchi, R. Feederle, B. De Strooper, S. Schulte-Merker, E. Lammert, D. Moechars, B. Schmid, S. F. Lichtenthaler

Date Published: 18th Jun 2024

Publication Type: Journal

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.

Abstract (Expand)

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in … vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.

Authors: L. M. Bartos, S. V. Kirchleitner, Z. I. Kolabas, S. Quach, A. Beck, J. Lorenz, J. Blobner, S. A. Mueller, S. Ulukaya, L. Hoeher, I. Horvath, K. Wind-Mark, A. Holzgreve, V. C. Ruf, L. Gold, L. H. Kunze, S. T. Kunte, P. Beumers, H. E. Park, M. Antons, A. Zatcepin, N. Briel, L. Hoermann, R. Schaefer, D. Messerer, P. Bartenstein, M. J. Riemenschneider, S. Lindner, S. Ziegler, J. Herms, S. F. Lichtenthaler, A. Erturk, J. C. Tonn, L. von Baumgarten, N. L. Albert, M. Brendel

Date Published: 27th Oct 2023

Publication Type: Journal

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Abstract (Expand)

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here … we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Authors: Y. H. Tai, D. Engels, G. Locatelli, I. Emmanouilidis, C. Fecher, D. Theodorou, S. A. Muller, S. Licht-Mayer, M. Kreutzfeldt, I. Wagner, N. P. de Mello, S. N. Gkotzamani, L. Trovo, A. Kendirli, A. Aljovic, M. O. Breckwoldt, R. Naumann, F. M. Bareyre, F. Perocchi, D. Mahad, D. Merkler, S. F. Lichtenthaler, M. Kerschensteiner, T. Misgeld

Date Published: 25th Aug 2023

Publication Type: Journal

Reactivated endogenous retroviruses promote protein aggregate spreading.

Abstract (Expand)

Prion-like spreading of protein misfolding is a characteristic of neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence … accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. We show that upregulation of endogenous retroviruses drastically increases the dissemination of protein aggregates between cells in culture, a process that can be inhibited by targeting the viral envelope protein or viral protein processing. Human endogenous retrovirus envelopes of four different clades also elevate intercellular spreading of proteopathic seeds, including pathological Tau. Our data support a role of endogenous retroviruses in protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.

Authors: S. Liu, S. E. Heumuller, A. Hossinger, S. A. Muller, O. Buravlova, S. F. Lichtenthaler, P. Denner, I. M. Vorberg

Date Published: 18th Aug 2023

Publication Type: Journal

The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

Abstract (Expand)

BACKGROUND: The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation … of unknown physiological BACE1 substrates. METHODS: To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. RESULTS: Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. CONCLUSION: BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.

Authors: S. A. Muller, M. D. Shmueli, X. Feng, J. Tushaus, N. Schumacher, R. Clark, B. E. Smith, A. Chi, S. Rose-John, M. E. Kennedy, S. F. Lichtenthaler

Date Published: 21st Feb 2023

Publication Type: Journal

Beneficial Effect of ACI-24 Vaccination on Abeta Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse Model.

Abstract (Expand)

Amyloid-beta (Abeta) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Abeta plaques, but their phagocytic capacity … declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Abeta targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Abeta plaque load, Abeta plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Abeta plaques, we observed a more ramified morphology of Abeta plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Abeta plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Abeta targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.

Authors: J. Rudan Njavro, M. Vukicevic, E. Fiorini, L. Dinkel, S. A. Muller, A. Berghofer, C. Bordier, S. Kozlov, A. Halle, K. Buschmann, A. Capell, C. Giudici, M. Willem, R. Feederle, S. F. Lichtenthaler, C. Babolin, P. Montanari, A. Pfeifer, M. Kosco-Vilbois, S. Tahirovic

Date Published: 24th Dec 2022

Publication Type: Journal

Spatial proteomics in three-dimensional intact specimens.

Abstract (Expand)

Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of large biological specimens … imaged in 3D are lacking. Here, we present DISCO-MS, a technology that combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry. DISCO-MS yielded proteome data indistinguishable from uncleared samples in both rodent and human tissues. We used DISCO-MS to investigate microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer's disease. DISCO-bot robotic sample extraction enabled us to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. DISCO-MS enables unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D, identifying diagnostic and therapeutic opportunities for complex diseases. VIDEO ABSTRACT.

Authors: H. S. Bhatia, A. D. Brunner, F. Ozturk, S. Kapoor, Z. Rong, H. Mai, M. Thielert, M. Ali, R. Al-Maskari, J. C. Paetzold, F. Kofler, M. I. Todorov, M. Molbay, Z. I. Kolabas, M. Negwer, L. Hoeher, H. Steinke, A. Dima, B. Gupta, D. Kaltenecker, O. S. Caliskan, D. Brandt, N. Krahmer, S. Muller, S. F. Lichtenthaler, F. Hellal, I. Bechmann, B. Menze, F. Theis, M. Mann, A. Erturk

Date Published: 22nd Dec 2022

Publication Type: Journal

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