TY  - JOUR
AU  - Willem, Michael
AU  - Tahirovic, Sabina
AU  - Busche, Marc Aurel
AU  - Ovsepian, Saak V
AU  - Chafai, Magda
AU  - Kootar, Scherazad
AU  - Hornburg, Daniel
AU  - Evans, Lewis D B
AU  - Moore, Steven
AU  - Daria, Anna
AU  - Hampel, Heike
AU  - Müller, Veronika
AU  - Giudici, Camilla
AU  - Nuscher, Brigitte
AU  - Wenninger-Weinzierl, Andrea
AU  - Kremmer, Elisabeth
AU  - Heneka, Michael T
AU  - Thal, Dietmar R
AU  - Giedraitis, Vilmantas
AU  - Lannfelt, Lars
AU  - Müller, Ulrike
AU  - Livesey, Frederick J
AU  - Meissner, Felix
AU  - Herms, Jochen
AU  - Konnerth, Arthur
AU  - Marie, Hélène
AU  - Haass, Christian
TI  - η-Secretase processing of APP inhibits neuronal activity in the hippocampus.
JO  - Nature 
VL  - 526
IS  - 7573
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group65848
M1  - DZNE-2020-04480
SP  - 443-447
PY  - 2015
AB  - 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.
KW  - ADAM Proteins: metabolism
KW  - ADAM10 Protein
KW  - Alzheimer Disease: enzymology
KW  - Alzheimer Disease: metabolism
KW  - Amyloid Precursor Protein Secretases: antagonists & inhibitors
KW  - Amyloid Precursor Protein Secretases: cerebrospinal fluid
KW  - Amyloid Precursor Protein Secretases: deficiency
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Amyloid beta-Protein Precursor: cerebrospinal fluid
KW  - Amyloid beta-Protein Precursor: chemistry
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Animals
KW  - Aspartic Acid Endopeptidases: antagonists & inhibitors
KW  - Aspartic Acid Endopeptidases: deficiency
KW  - Aspartic Acid Endopeptidases: genetics
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Calcium Signaling
KW  - Disease Models, Animal
KW  - Female
KW  - Hippocampus: cytology
KW  - Hippocampus: enzymology
KW  - Hippocampus: physiology
KW  - Humans
KW  - In Vitro Techniques
KW  - Long-Term Potentiation
KW  - Male
KW  - Matrix Metalloproteinases, Membrane-Associated: deficiency
KW  - Matrix Metalloproteinases, Membrane-Associated: metabolism
KW  - Membrane Proteins: metabolism
KW  - Mice
KW  - Molecular Weight
KW  - Neurites: enzymology
KW  - Neurites: metabolism
KW  - Neurons: enzymology
KW  - Neurons: physiology
KW  - Peptide Fragments: chemistry
KW  - Peptide Fragments: metabolism
KW  - Plaque, Amyloid
KW  - Protein Processing, Post-Translational
KW  - Proteolysis
KW  - Single-Cell Analysis
KW  - APP protein, human (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - BACE1 protein, human (NLM Chemicals)
KW  - Bace1 protein, mouse (NLM Chemicals)
KW  - ADAM Proteins (NLM Chemicals)
KW  - Matrix Metalloproteinases, Membrane-Associated (NLM Chemicals)
KW  - Mmp24 protein, mouse (NLM Chemicals)
KW  - ADAM10 Protein (NLM Chemicals)
KW  - ADAM10 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26322584
C2  - pmc:PMC6570618
DO  - DOI:10.1038/nature14864
UR  - https://pub.dzne.de/record/138158
ER  -