%0 Journal Article
%A Willem, Michael
%A Tahirovic, Sabina
%A Busche, Marc Aurel
%A Ovsepian, Saak V
%A Chafai, Magda
%A Kootar, Scherazad
%A Hornburg, Daniel
%A Evans, Lewis D B
%A Moore, Steven
%A Daria, Anna
%A Hampel, Heike
%A Müller, Veronika
%A Giudici, Camilla
%A Nuscher, Brigitte
%A Wenninger-Weinzierl, Andrea
%A Kremmer, Elisabeth
%A Heneka, Michael T
%A Thal, Dietmar R
%A Giedraitis, Vilmantas
%A Lannfelt, Lars
%A Müller, Ulrike
%A Livesey, Frederick J
%A Meissner, Felix
%A Herms, Jochen
%A Konnerth, Arthur
%A Marie, Hélène
%A Haass, Christian
%T η-Secretase processing of APP inhibits neuronal activity in the hippocampus.
%J Nature 
%V 526
%N 7573
%@ 0028-0836
%C London [u.a.]
%I Nature Publ. Group65848
%M DZNE-2020-04480
%P 443-447
%D 2015
%X 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.
%K ADAM Proteins: metabolism
%K ADAM10 Protein
%K Alzheimer Disease: enzymology
%K Alzheimer Disease: metabolism
%K Amyloid Precursor Protein Secretases: antagonists & inhibitors
%K Amyloid Precursor Protein Secretases: cerebrospinal fluid
%K Amyloid Precursor Protein Secretases: deficiency
%K Amyloid Precursor Protein Secretases: genetics
%K Amyloid Precursor Protein Secretases: metabolism
%K Amyloid beta-Protein Precursor: cerebrospinal fluid
%K Amyloid beta-Protein Precursor: chemistry
%K Amyloid beta-Protein Precursor: genetics
%K Amyloid beta-Protein Precursor: metabolism
%K Animals
%K Aspartic Acid Endopeptidases: antagonists & inhibitors
%K Aspartic Acid Endopeptidases: deficiency
%K Aspartic Acid Endopeptidases: genetics
%K Aspartic Acid Endopeptidases: metabolism
%K Calcium Signaling
%K Disease Models, Animal
%K Female
%K Hippocampus: cytology
%K Hippocampus: enzymology
%K Hippocampus: physiology
%K Humans
%K In Vitro Techniques
%K Long-Term Potentiation
%K Male
%K Matrix Metalloproteinases, Membrane-Associated: deficiency
%K Matrix Metalloproteinases, Membrane-Associated: metabolism
%K Membrane Proteins: metabolism
%K Mice
%K Molecular Weight
%K Neurites: enzymology
%K Neurites: metabolism
%K Neurons: enzymology
%K Neurons: physiology
%K Peptide Fragments: chemistry
%K Peptide Fragments: metabolism
%K Plaque, Amyloid
%K Protein Processing, Post-Translational
%K Proteolysis
%K Single-Cell Analysis
%K APP protein, human (NLM Chemicals)
%K Amyloid beta-Protein Precursor (NLM Chemicals)
%K Membrane Proteins (NLM Chemicals)
%K Peptide Fragments (NLM Chemicals)
%K Amyloid Precursor Protein Secretases (NLM Chemicals)
%K Aspartic Acid Endopeptidases (NLM Chemicals)
%K BACE1 protein, human (NLM Chemicals)
%K Bace1 protein, mouse (NLM Chemicals)
%K ADAM Proteins (NLM Chemicals)
%K Matrix Metalloproteinases, Membrane-Associated (NLM Chemicals)
%K Mmp24 protein, mouse (NLM Chemicals)
%K ADAM10 Protein (NLM Chemicals)
%K ADAM10 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:26322584
%2 pmc:PMC6570618
%R 10.1038/nature14864
%U https://pub.dzne.de/record/138158