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Author: Stefan Lichtenthaler3
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

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

Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins.

Abstract (Expand)

Members of the GxGD-type intramembrane aspartyl proteases have emerged as key players not only in fundamental cellular processes such as B-cell development or protein glycosylation, but also in development … of pathologies, such as Alzheimer's disease or hepatitis virus infections. However, one member of this protease family, signal peptide peptidase-like 2c (SPPL2c), remains orphan and its capability of proteolysis as well as its physiological function is still enigmatic. Here, we demonstrate that SPPL2c is catalytically active and identify a variety of SPPL2c candidate substrates using proteomics. The majority of the SPPL2c candidate substrates cluster to the biological process of vesicular trafficking. Analysis of selected SNARE proteins reveals proteolytic processing by SPPL2c that impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Together with a strikingly high physiological SPPL2c expression in testis, our data suggest involvement of SPPL2c in acrosome formation during spermatogenesis.

Authors: A. A. Papadopoulou, S. A. Muller, T. Mentrup, M. D. Shmueli, J. Niemeyer, M. Haug-Kroper, J. von Blume, A. Mayerhofer, R. Feederle, B. Schroder, S. F. Lichtenthaler, R. Fluhrer

Date Published: 9th Feb 2019

Publication Type: Journal

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