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| 001 | 138158 | ||
| 005 | 20240321220401.0 | ||
| 024 | 7 | _ | |a 10.1038/nature14864 |2 doi |
| 024 | 7 | _ | |a pmid:26322584 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC6570618 |2 pmc |
| 024 | 7 | _ | |a 0028-0836 |2 ISSN |
| 024 | 7 | _ | |a 1476-4687 |2 ISSN |
| 024 | 7 | _ | |a altmetric:4455229 |2 altmetric |
| 037 | _ | _ | |a DZNE-2020-04480 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 500 |
| 100 | 1 | _ | |a Willem, Michael |0 P:(DE-HGF)0 |b 0 |e Corresponding author |
| 245 | _ | _ | |a η-Secretase processing of APP inhibits neuronal activity in the hippocampus. |
| 260 | _ | _ | |a London [u.a.] |c 2015 |b Nature Publ. Group65848 |
| 264 | _ | 1 | |3 online |2 Crossref |b Springer Science and Business Media LLC |c 2015-08-31 |
| 264 | _ | 1 | |3 print |2 Crossref |b Springer Science and Business Media LLC |c 2015-10-01 |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1591962874_16338 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 342 - Disease Mechanisms and Model Systems (POF3-342) |0 G:(DE-HGF)POF3-342 |c POF3-342 |f POF III |x 0 |
| 536 | _ | _ | |a 344 - Clinical and Health Care Research (POF3-344) |0 G:(DE-HGF)POF3-344 |c POF3-344 |f POF III |x 1 |
| 542 | _ | _ | |i 2015-08-31 |2 Crossref |u http://www.springer.com/tdm |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a APP protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a Amyloid beta-Protein Precursor |2 NLM Chemicals |
| 650 | _ | 7 | |a Membrane Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Peptide Fragments |2 NLM Chemicals |
| 650 | _ | 7 | |a Amyloid Precursor Protein Secretases |0 EC 3.4.- |2 NLM Chemicals |
| 650 | _ | 7 | |a Aspartic Acid Endopeptidases |0 EC 3.4.23.- |2 NLM Chemicals |
| 650 | _ | 7 | |a BACE1 protein, human |0 EC 3.4.23.46 |2 NLM Chemicals |
| 650 | _ | 7 | |a Bace1 protein, mouse |0 EC 3.4.23.46 |2 NLM Chemicals |
| 650 | _ | 7 | |a ADAM Proteins |0 EC 3.4.24.- |2 NLM Chemicals |
| 650 | _ | 7 | |a Matrix Metalloproteinases, Membrane-Associated |0 EC 3.4.24.- |2 NLM Chemicals |
| 650 | _ | 7 | |a Mmp24 protein, mouse |0 EC 3.4.24.- |2 NLM Chemicals |
| 650 | _ | 7 | |a ADAM10 Protein |0 EC 3.4.24.81 |2 NLM Chemicals |
| 650 | _ | 7 | |a ADAM10 protein, human |0 EC 3.4.24.81 |2 NLM Chemicals |
| 650 | _ | 2 | |a ADAM Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a ADAM10 Protein |2 MeSH |
| 650 | _ | 2 | |a Alzheimer Disease: enzymology |2 MeSH |
| 650 | _ | 2 | |a Alzheimer Disease: metabolism |2 MeSH |
| 650 | _ | 2 | |a Amyloid Precursor Protein Secretases: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Amyloid Precursor Protein Secretases: cerebrospinal fluid |2 MeSH |
| 650 | _ | 2 | |a Amyloid Precursor Protein Secretases: deficiency |2 MeSH |
| 650 | _ | 2 | |a Amyloid Precursor Protein Secretases: genetics |2 MeSH |
| 650 | _ | 2 | |a Amyloid Precursor Protein Secretases: metabolism |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Protein Precursor: cerebrospinal fluid |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Protein Precursor: chemistry |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Protein Precursor: genetics |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Protein Precursor: metabolism |2 MeSH |
| 650 | _ | 2 | |a Animals |2 MeSH |
| 650 | _ | 2 | |a Aspartic Acid Endopeptidases: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Aspartic Acid Endopeptidases: deficiency |2 MeSH |
| 650 | _ | 2 | |a Aspartic Acid Endopeptidases: genetics |2 MeSH |
| 650 | _ | 2 | |a Aspartic Acid Endopeptidases: metabolism |2 MeSH |
| 650 | _ | 2 | |a Calcium Signaling |2 MeSH |
| 650 | _ | 2 | |a Disease Models, Animal |2 MeSH |
| 650 | _ | 2 | |a Female |2 MeSH |
| 650 | _ | 2 | |a Hippocampus: cytology |2 MeSH |
| 650 | _ | 2 | |a Hippocampus: enzymology |2 MeSH |
| 650 | _ | 2 | |a Hippocampus: physiology |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a In Vitro Techniques |2 MeSH |
| 650 | _ | 2 | |a Long-Term Potentiation |2 MeSH |
| 650 | _ | 2 | |a Male |2 MeSH |
| 650 | _ | 2 | |a Matrix Metalloproteinases, Membrane-Associated: deficiency |2 MeSH |
| 650 | _ | 2 | |a Matrix Metalloproteinases, Membrane-Associated: metabolism |2 MeSH |
| 650 | _ | 2 | |a Membrane Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Mice |2 MeSH |
| 650 | _ | 2 | |a Molecular Weight |2 MeSH |
| 650 | _ | 2 | |a Neurites: enzymology |2 MeSH |
| 650 | _ | 2 | |a Neurites: metabolism |2 MeSH |
| 650 | _ | 2 | |a Neurons: enzymology |2 MeSH |
| 650 | _ | 2 | |a Neurons: physiology |2 MeSH |
| 650 | _ | 2 | |a Peptide Fragments: chemistry |2 MeSH |
| 650 | _ | 2 | |a Peptide Fragments: metabolism |2 MeSH |
| 650 | _ | 2 | |a Plaque, Amyloid |2 MeSH |
| 650 | _ | 2 | |a Protein Processing, Post-Translational |2 MeSH |
| 650 | _ | 2 | |a Proteolysis |2 MeSH |
| 650 | _ | 2 | |a Single-Cell Analysis |2 MeSH |
| 700 | 1 | _ | |a Tahirovic, Sabina |0 P:(DE-2719)2442036 |b 1 |u dzne |
| 700 | 1 | _ | |a Busche, Marc Aurel |b 2 |
| 700 | 1 | _ | |a Ovsepian, Saak V |0 P:(DE-2719)9000407 |b 3 |u dzne |
| 700 | 1 | _ | |a Chafai, Magda |b 4 |
| 700 | 1 | _ | |a Kootar, Scherazad |b 5 |
| 700 | 1 | _ | |a Hornburg, Daniel |b 6 |
| 700 | 1 | _ | |a Evans, Lewis D B |b 7 |
| 700 | 1 | _ | |a Moore, Steven |b 8 |
| 700 | 1 | _ | |a Daria, Anna |b 9 |
| 700 | 1 | _ | |a Hampel, Heike |b 10 |
| 700 | 1 | _ | |a Müller, Veronika |b 11 |
| 700 | 1 | _ | |a Giudici, Camilla |0 P:(DE-HGF)0 |b 12 |
| 700 | 1 | _ | |a Nuscher, Brigitte |0 P:(DE-HGF)0 |b 13 |
| 700 | 1 | _ | |a Wenninger-Weinzierl, Andrea |0 P:(DE-2719)2810261 |b 14 |u dzne |
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| 700 | 1 | _ | |a Heneka, Michael T |0 P:(DE-2719)2000008 |b 16 |u dzne |
| 700 | 1 | _ | |a Thal, Dietmar R |b 17 |
| 700 | 1 | _ | |a Giedraitis, Vilmantas |b 18 |
| 700 | 1 | _ | |a Lannfelt, Lars |b 19 |
| 700 | 1 | _ | |a Müller, Ulrike |b 20 |
| 700 | 1 | _ | |a Livesey, Frederick J |b 21 |
| 700 | 1 | _ | |a Meissner, Felix |b 22 |
| 700 | 1 | _ | |a Herms, Jochen |0 P:(DE-2719)2810441 |b 23 |u dzne |
| 700 | 1 | _ | |a Konnerth, Arthur |b 24 |
| 700 | 1 | _ | |a Marie, Hélène |b 25 |
| 700 | 1 | _ | |a Haass, Christian |0 P:(DE-2719)2202037 |b 26 |e Last author |u dzne |
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