title: η-Secretase processing of APP inhibits neuronal activity in the hippocampus.
abstract: Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation 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 APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.
authors: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Michael
authors: M
authors: Willem
authors: German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany.
authors: Sabina
authors: S
authors: Tahirovic
authors: Department of Psychiatry and Psychotherapy, Technische Universität München, 81675 Munich, Germany.|Institute of Neuroscience, Technische Universität München, 80802 Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Marc Aurel
authors: MA
authors: Busche
authors: German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany.
authors: Saak V
authors: SV
authors: Ovsepian
authors: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, 06560 Valbonne, France.
authors: Magda
authors: M
authors: Chafai
authors: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, 06560 Valbonne, France.
authors: Scherazad
authors: S
authors: Kootar
authors: Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors: Daniel
authors: D
authors: Hornburg
authors: Gurdon Institute, Cambridge Stem Cell Institute &Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
authors: Lewis D B
authors: LD
authors: Evans
authors: Gurdon Institute, Cambridge Stem Cell Institute &Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
authors: Steven
authors: S
authors: Moore
authors: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Anna
authors: A
authors: Daria
authors: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Heike
authors: H
authors: Hampel
authors: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Veronika
authors: V
authors: Müller
authors: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Camilla
authors: C
authors: Giudici
authors: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Brigitte
authors: B
authors: Nuscher
authors: German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany.
authors: Andrea
authors: A
authors: Wenninger-Weinzierl
authors: German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.|Institute of Molecular Immunology, German Research Center for Environmental Health, 81377 Munich, Germany.
authors: Elisabeth
authors: E
authors: Kremmer
authors: Department of Neurology, Clinical Neuroscience Unit, University of Bonn, 53127 Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE) Bonn, 53175 Bonn, Germany.
authors: Michael T
authors: MT
authors: Heneka
authors: Institute of Pathology - Laboratory for Neuropathology, University of Ulm, 89081 Ulm, Germany.
authors: Dietmar R
authors: DR
authors: Thal
authors: Department of Public Health/Geriatrics, Uppsala University, 751 85 Uppsala, Sweden.
authors: Vilmantas
authors: V
authors: Giedraitis
authors: Department of Public Health/Geriatrics, Uppsala University, 751 85 Uppsala, Sweden.
authors: Lars
authors: L
authors: Lannfelt
authors: Institute for Pharmacy and Molecular Biotechnology IPMB, Functional Genomics, University of Heidelberg, 69120 Heidelberg, Germany.
authors: Ulrike
authors: U
authors: Müller
authors: Gurdon Institute, Cambridge Stem Cell Institute &Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
authors: Frederick J
authors: FJ
authors: Livesey
authors: Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors: Felix
authors: F
authors: Meissner
authors: German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany.
authors: Jochen
authors: J
authors: Herms
authors: Institute of Neuroscience, Technische Universität München, 80802 Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Arthur
authors: A
authors: Konnerth
authors: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, 06560 Valbonne, France.
authors: Hélène
authors: H
authors: Marie
authors: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors: Christian
authors: C
authors: Haass
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation; D008297:Male; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000172:deficiency / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D016501:Neurites / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D058225:Plaque, Amyloid; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D059010:Single-Cell Analysis
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D053504:Matrix Metalloproteinases, Membrane-Associated; C118502:Mmp24 protein, mouse; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human