Consequences of Amyloid-β Deficiency for the Liver.

Autor: Buniatian GH; Department of Clinical Pharmacology, University Hospital of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany., Schwinghammer U; Department of Clinical Pharmacology, University Hospital of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany., Tremmel R; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.; University of Tuebingen, 72074, Tuebingen, Germany., Cynis H; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Weinbergweg 22, 06120, Halle (Saale), Germany.; Junior Research Group, Immunomodulation in Pathophysiological Processes, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, 06120, Halle (Saale), Germany., Weiss TS; Children's University Hospital (KUNO), University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany., Weiskirchen R; Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany., Lauschke VM; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.; University of Tuebingen, 72074, Tuebingen, Germany.; Department of Physiology and Pharmacology Karolinska Institute, Stockholm, 171 77, Sweden., Youhanna S; Department of Physiology and Pharmacology Karolinska Institute, Stockholm, 171 77, Sweden., Ramos I; Innovative Technologies in Biological Systems SL (INNOPROT), Bizkaia, Derio, 48160, Spain., Valcarcel M; Innovative Technologies in Biological Systems SL (INNOPROT), Bizkaia, Derio, 48160, Spain., Seferyan T; H. Buniatian Institute of Biochemistry, National Academy of Sciences of the Republic of Armenia (NAS RA), 5/1 Paruir Sevak St., Yerevan, 0014, Armenia., Rahfeld JU; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Weinbergweg 22, 06120, Halle (Saale), Germany., Rieckmann V; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Weinbergweg 22, 06120, Halle (Saale), Germany., Klein K; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.; University of Tuebingen, 72074, Tuebingen, Germany., Buadze M; Department of Clinical Pharmacology, University Hospital of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany., Weber V; Department of Clinical Pharmacology, University Hospital of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany., Kolak V; Department of Clinical Pharmacology, University Hospital of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany., Gebhardt R; Rudolf-Schönheimer Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Johannisstraße 30, 04103, Leipzig, Germany., Friedman SL; Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA., Müller UC; Institute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany., Schwab M; Department of Clinical Pharmacology, University Hospital of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany.; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.; Departments of Biochemistry and Clinical Pharmacology, and Neuroscience Laboratory, Yerevan State Medical University, 2- Koryun St, Yerevan, 0025, Armenia.; Cluster of Excellence iFIT (EXC2180) 'Image-guided and Functionally Instructed Tumor Therapies', University of Tübingen, 72076, Tübingen, Germany., Danielyan L; Department of Clinical Pharmacology, University Hospital of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany.; Departments of Biochemistry and Clinical Pharmacology, and Neuroscience Laboratory, Yerevan State Medical University, 2- Koryun St, Yerevan, 0025, Armenia.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 May; Vol. 11 (18), pp. e2307734. Date of Electronic Publication: 2024 Mar 02.
DOI: 10.1002/advs.202307734
Abstrakt: The hepatic content of amyloid beta (Aβ) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aβ deficiency in the liver. This is especially relevant in view of recent advances in anti-Aβ therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aβ in transgenic AD mice immunized with Aβ antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP-KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha-actin, and collagen type I. Aβ absence in APP-KO and deficiency in immunized mice lead to strong activation of transforming growth factor-β (TGFβ), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial-mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aβ42 in transgenic AD mice and neprilysin inhibitor LBQ657-treated wild-type mice protect the liver against carbon tetrachloride (CCl 4 )-induced injury. Transcriptomic analysis of CCl 4 -treated transgenic AD mouse livers uncovers the regulatory effects of Aβ42 on mitochondrial function, lipid metabolism, and its onco-suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aβ as an indispensable regulator of cell-cell interactions in healthy liver and a powerful protector against liver fibrosis.
(© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje