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  • Willem, MichaelUniv Munich, Biomed Ctr BMC, D-81377 Munich, Germany. (författare)

eta-Secretase processing of APP inhibits neuronal activity in the hippocampus

  • Artikel/kapitelEngelska2015

Förlag, utgivningsår, omfång ...

  • 2015-08-31
  • Springer Science and Business Media LLC,2015
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-265812
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-265812URI
  • https://doi.org/10.1038/nature14864DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide(1). Two principal physiological pathways either prevent or promote amyloid-beta generation from its precursor, beta-amyloid precursor protein (APP), in a competitive manne(r)1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo(2). 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-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (beta-site APP cleaving enzyme 1), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as g-secretase activity. g-Secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A eta peptides (termed A eta-alpha and A eta-beta). CTFs produced by g-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-eta and A eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A eta-alpha 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 A eta-alpha. 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Tahirovic, SabinaGerman Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany. (författare)
  • Busche, Marc AurelTech Univ Munich, Dept Psychiat & Psychotherapy, D-81675 Munich, Germany.;Tech Univ Munich, Inst Neurosci, D-80802 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany. (författare)
  • Ovsepian, Saak V.German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany. (författare)
  • Chafai, MagdaUniv Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France. (författare)
  • Kootar, ScherazadUniv Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France. (författare)
  • Hornburg, DanielMax Planck Inst Biochem, D-82152 Martinsried, Germany. (författare)
  • Evans, Lewis D. B.Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England. (författare)
  • Moore, StevenUniv Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England. (författare)
  • Daria, AnnaUniv Munich, Biomed Ctr BMC, D-81377 Munich, Germany. (författare)
  • Hampel, HeikeUniv Munich, Biomed Ctr BMC, D-81377 Munich, Germany. (författare)
  • Mueller, VeronikaUniv Munich, Biomed Ctr BMC, D-81377 Munich, Germany. (författare)
  • Giudici, CamillaUniv Munich, Biomed Ctr BMC, D-81377 Munich, Germany. (författare)
  • Nuscher, BrigitteUniv Munich, Biomed Ctr BMC, D-81377 Munich, Germany. (författare)
  • Wenninger-Weinzierl, AndreaGerman Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany. (författare)
  • Kremmer, ElisabethGerman Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany.;German Res Ctr Environm Hlth, Inst Mol Immunol, D-81377 Munich, Germany. (författare)
  • Heneka, Michael T.Univ Bonn, Clin Neurosci Unit, Dept Neurol, D-53127 Bonn, Germany.;German Ctr Neurodegenerat Dis DZNE Bonn, D-53175 Bonn, Germany. (författare)
  • Thal, Dietmar R.Univ Ulm, Inst Pathol, Neuropathol Lab, D-89081 Ulm, Germany. (författare)
  • Giedraitis, VilmantasUppsala universitet,Geriatrik(Swepub:uu)vigie517 (författare)
  • Lannfelt, LarsUppsala universitet,Geriatrik(Swepub:uu)lalan021 (författare)
  • Mueller, UlrikeHeidelberg Univ, Funct Genom, Inst Pharm & Mol Biotechnol IPMB, D-69120 Heidelberg, Germany. (författare)
  • Livesey, Frederick J.Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England. (författare)
  • Meissner, FelixMax Planck Inst Biochem, D-82152 Martinsried, Germany. (författare)
  • Herms, JochenGerman Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany. (författare)
  • Konnerth, ArthurTech Univ Munich, Inst Neurosci, D-80802 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany. (författare)
  • Marie, HeleneUniv Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France. (författare)
  • Haass, ChristianUniv Munich, Biomed Ctr BMC, D-81377 Munich, Germany.;German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany. (författare)
  • Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany. (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Nature: Springer Science and Business Media LLC526:7573, s. 443-4470028-08361476-4687

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