1. η-Secretase processing of APP inhibits neuronal activity in the hippocampus
- Author
-
Scherazad Kootar, Marc Aurel Busche, Steven Moore, Lewis D. B. Evans, Sabina Tahirovic, Daniel Hornburg, Dietmar Rudolf Thal, Anna Daria, Hélène Marie, Jochen Herms, Frederick J. Livesey, Christian Haass, Elisabeth Kremmer, Vilmantas Giedraitis, Felix Meissner, Heike Hampel, Veronika Müller, Ulrike Müller, Michael Willem, Camilla Giudici, Saak V. Ovsepian, Michael T. Heneka, Brigitte Nuscher, Lars Lannfelt, Andrea Wenninger-Weinzierl, Arthur Konnerth, Magda Chafai, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Equipe de Recherche en Syntaxe et Sémantique (ERSS), Université Toulouse - Jean Jaurès (UT2J)-Université Bordeaux Montaigne-Centre National de la Recherche Scientifique (CNRS), European IPF Registry and Biobank (eurIPFreg/bank), Institut für Molekulare Immunologie, GSF, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Department of Experimental Systems Immunology [Martinsried, Allemagne], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Ludwig-Maximilians-Universität München (LMU), Institute of Neuroscience and Center for Integrated Protein Science, and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)
- Subjects
enzymology [Neurites] ,Male ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,ADAM10 ,Long-Term Potentiation ,physiology [Hippocampus] ,genetics [Amyloid Precursor Protein Secretases] ,Plaque, Amyloid ,antagonists & inhibitors [Amyloid Precursor Protein Secretases] ,Molecular neuroscience ,Hippocampal formation ,Hippocampus ,APP protein, human ,ADAM10 Protein ,Mice ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,metabolism [Amyloid beta-Protein Precursor] ,metabolism [Peptide Fragments] ,Aspartic Acid Endopeptidases ,Premovement neuronal activity ,chemistry [Amyloid beta-Protein Precursor] ,ComputingMilieux_MISCELLANEOUS ,Neurons ,enzymology [Neurons] ,0303 health sciences ,Multidisciplinary ,biology ,metabolism [Neurites] ,Long-term potentiation ,deficiency [Amyloid Precursor Protein Secretases] ,antagonists & inhibitors [Aspartic Acid Endopeptidases] ,metabolism [Aspartic Acid Endopeptidases] ,physiology [Neurons] ,Research Highlight ,cerebrospinal fluid [Amyloid beta-Protein Precursor] ,Ectodomain ,Biochemistry ,genetics [Amyloid beta-Protein Precursor] ,Female ,ddc:500 ,Single-Cell Analysis ,metabolism [Alzheimer Disease] ,metabolism [Matrix Metalloproteinases, Membrane-Associated] ,Matrix Metalloproteinases, Membrane-Associated ,Bace1 protein, mouse ,ADAM10 protein, human ,In Vitro Techniques ,Article ,03 medical and health sciences ,enzymology [Hippocampus] ,Calcium imaging ,cerebrospinal fluid [Amyloid Precursor Protein Secretases] ,Alzheimer Disease ,BACE1 protein, human ,mental disorders ,deficiency [Matrix Metalloproteinases, Membrane-Associated] ,Neurites ,Animals ,Humans ,Calcium Signaling ,deficiency [Aspartic Acid Endopeptidases] ,Mmp24 protein, mouse ,030304 developmental biology ,enzymology [Alzheimer Disease] ,Membrane Proteins ,metabolism [Amyloid Precursor Protein Secretases] ,Peptide Fragments ,Molecular Weight ,ADAM Proteins ,Disease Models, Animal ,genetics [Aspartic Acid Endopeptidases] ,metabolism [ADAM Proteins] ,cytology [Hippocampus] ,chemistry [Peptide Fragments] ,Proteolysis ,biology.protein ,Amyloid Precursor Protein Secretases ,Protein Processing, Post-Translational ,Amyloid precursor protein secretase ,metabolism [Membrane Proteins] ,030217 neurology & neurosurgery - Abstract
Alzheimer's disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid β-peptide (Aβ)1. Two principal physiological pathways either prevent or promote Aβ generation from its precursor (amyloid precursor protein; APP) in a competitive manner1. Modulation of the amyloidogenic pathway is currently exploited by anti-Aβ therapeutic strategies2. Although APP processing has been studied in great detail, unknown proteolytic events appear to hinder stoichiometric analyses of APP metabolism in vivo3. We now identified higher molecular weight C-terminal fragments of APP (CTF-η) in addition to the long-known α- and β-secretase (a disintegrin and metalloproteinase; ADAM10 and β-site APP cleaving enzyme 1; BACE1) generated CTF-α and CTF-β. Generation of CTF-η is mediated in part by membrane bound matrix-metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504/505 of APP(695) releasing a truncated, soluble APP ectodomain (sAPP-η). Upon shedding of sAPP-η CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (Aη-α and Aη-β). Aη peptides are therefore distinct from N-terminally extended Aβ variants4,5, since they do not extend to the γ-secretase cleavage sites. η-Secretase produced CTFs are enriched in dystrophic neurites in an AD mouse model and human AD brains6. Genetic and pharmacological inhibition of BACE1 activity results in a robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor hippocampal long-term potentiation (LTP) was reduced. Strikingly, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, LTP was lowered. Furthermore, in vivo single cell two-photon calcium imaging revealed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major physiologically relevant APP processing pathway but may also suggest potential translational relevance for therapeutic strategies targeting APP processing.
- Published
- 2015
- Full Text
- View/download PDF