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000138158 0247_ $$2doi$$a10.1038/nature14864
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000138158 0247_ $$2pmc$$apmc:PMC6570618
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000138158 037__ $$aDZNE-2020-04480
000138158 041__ $$aEnglish
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000138158 1001_ $$0P:(DE-HGF)0$$aWillem, Michael$$b0$$eCorresponding author
000138158 245__ $$aη-Secretase processing of APP inhibits neuronal activity in the hippocampus.
000138158 260__ $$aLondon [u.a.]$$bNature Publ. Group65848$$c2015
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000138158 520__ $$aAlzheimer 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.
000138158 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000138158 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x1
000138158 542__ $$2Crossref$$i2015-08-31$$uhttp://www.springer.com/tdm
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000138158 650_7 $$2NLM Chemicals$$aAPP protein, human
000138158 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000138158 650_7 $$2NLM Chemicals$$aMembrane Proteins
000138158 650_7 $$2NLM Chemicals$$aPeptide Fragments
000138158 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000138158 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000138158 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBACE1 protein, human
000138158 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBace1 protein, mouse
000138158 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aADAM Proteins
000138158 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aMatrix Metalloproteinases, Membrane-Associated
000138158 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aMmp24 protein, mouse
000138158 650_7 $$0EC 3.4.24.81$$2NLM Chemicals$$aADAM10 Protein
000138158 650_7 $$0EC 3.4.24.81$$2NLM Chemicals$$aADAM10 protein, human
000138158 650_2 $$2MeSH$$aADAM Proteins: metabolism
000138158 650_2 $$2MeSH$$aADAM10 Protein
000138158 650_2 $$2MeSH$$aAlzheimer Disease: enzymology
000138158 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000138158 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: antagonists & inhibitors
000138158 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: cerebrospinal fluid
000138158 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: deficiency
000138158 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000138158 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000138158 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: cerebrospinal fluid
000138158 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: chemistry
000138158 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: genetics
000138158 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000138158 650_2 $$2MeSH$$aAnimals
000138158 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: antagonists & inhibitors
000138158 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: deficiency
000138158 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics
000138158 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: metabolism
000138158 650_2 $$2MeSH$$aCalcium Signaling
000138158 650_2 $$2MeSH$$aDisease Models, Animal
000138158 650_2 $$2MeSH$$aFemale
000138158 650_2 $$2MeSH$$aHippocampus: cytology
000138158 650_2 $$2MeSH$$aHippocampus: enzymology
000138158 650_2 $$2MeSH$$aHippocampus: physiology
000138158 650_2 $$2MeSH$$aHumans
000138158 650_2 $$2MeSH$$aIn Vitro Techniques
000138158 650_2 $$2MeSH$$aLong-Term Potentiation
000138158 650_2 $$2MeSH$$aMale
000138158 650_2 $$2MeSH$$aMatrix Metalloproteinases, Membrane-Associated: deficiency
000138158 650_2 $$2MeSH$$aMatrix Metalloproteinases, Membrane-Associated: metabolism
000138158 650_2 $$2MeSH$$aMembrane Proteins: metabolism
000138158 650_2 $$2MeSH$$aMice
000138158 650_2 $$2MeSH$$aMolecular Weight
000138158 650_2 $$2MeSH$$aNeurites: enzymology
000138158 650_2 $$2MeSH$$aNeurites: metabolism
000138158 650_2 $$2MeSH$$aNeurons: enzymology
000138158 650_2 $$2MeSH$$aNeurons: physiology
000138158 650_2 $$2MeSH$$aPeptide Fragments: chemistry
000138158 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000138158 650_2 $$2MeSH$$aPlaque, Amyloid
000138158 650_2 $$2MeSH$$aProtein Processing, Post-Translational
000138158 650_2 $$2MeSH$$aProteolysis
000138158 650_2 $$2MeSH$$aSingle-Cell Analysis
000138158 7001_ $$0P:(DE-2719)2442036$$aTahirovic, Sabina$$b1$$udzne
000138158 7001_ $$aBusche, Marc Aurel$$b2
000138158 7001_ $$0P:(DE-2719)9000407$$aOvsepian, Saak V$$b3$$udzne
000138158 7001_ $$aChafai, Magda$$b4
000138158 7001_ $$aKootar, Scherazad$$b5
000138158 7001_ $$aHornburg, Daniel$$b6
000138158 7001_ $$aEvans, Lewis D B$$b7
000138158 7001_ $$aMoore, Steven$$b8
000138158 7001_ $$aDaria, Anna$$b9
000138158 7001_ $$aHampel, Heike$$b10
000138158 7001_ $$aMüller, Veronika$$b11
000138158 7001_ $$0P:(DE-HGF)0$$aGiudici, Camilla$$b12
000138158 7001_ $$0P:(DE-HGF)0$$aNuscher, Brigitte$$b13
000138158 7001_ $$0P:(DE-2719)2810261$$aWenninger-Weinzierl, Andrea$$b14$$udzne
000138158 7001_ $$0P:(DE-2719)9000167$$aKremmer, Elisabeth$$b15$$udzne
000138158 7001_ $$0P:(DE-2719)2000008$$aHeneka, Michael T$$b16$$udzne
000138158 7001_ $$aThal, Dietmar R$$b17
000138158 7001_ $$aGiedraitis, Vilmantas$$b18
000138158 7001_ $$aLannfelt, Lars$$b19
000138158 7001_ $$aMüller, Ulrike$$b20
000138158 7001_ $$aLivesey, Frederick J$$b21
000138158 7001_ $$aMeissner, Felix$$b22
000138158 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b23$$udzne
000138158 7001_ $$aKonnerth, Arthur$$b24
000138158 7001_ $$aMarie, Hélène$$b25
000138158 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b26$$eLast author$$udzne
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