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eta-Secretase proce...
eta-Secretase processing of APP inhibits neuronal activity in the hippocampus
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- Willem, Michael (författare)
- Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
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- Tahirovic, Sabina (författare)
- German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.
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- Busche, Marc Aurel (författare)
- Tech 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.
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- Ovsepian, Saak V. (författare)
- German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.
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- Chafai, Magda (författare)
- Univ Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France.
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- Kootar, Scherazad (författare)
- Univ Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France.
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- Hornburg, Daniel (författare)
- Max Planck Inst Biochem, D-82152 Martinsried, Germany.
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- Evans, Lewis D. B. (författare)
- Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England.
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- Moore, Steven (författare)
- Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England.
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- Daria, Anna (författare)
- Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
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- Hampel, Heike (författare)
- Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
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- Mueller, Veronika (författare)
- Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
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- Giudici, Camilla (författare)
- Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
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- Nuscher, Brigitte (författare)
- Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.
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- Wenninger-Weinzierl, Andrea (författare)
- German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.
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- Kremmer, Elisabeth (författare)
- German 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.
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- Heneka, Michael T. (författare)
- Univ Bonn, Clin Neurosci Unit, Dept Neurol, D-53127 Bonn, Germany.;German Ctr Neurodegenerat Dis DZNE Bonn, D-53175 Bonn, Germany.
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- Thal, Dietmar R. (författare)
- Univ Ulm, Inst Pathol, Neuropathol Lab, D-89081 Ulm, Germany.
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- Giedraitis, Vilmantas (författare)
- Uppsala universitet,Geriatrik
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- Lannfelt, Lars (författare)
- Uppsala universitet,Geriatrik
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- Mueller, Ulrike (författare)
- Heidelberg Univ, Funct Genom, Inst Pharm & Mol Biotechnol IPMB, D-69120 Heidelberg, Germany.
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- Livesey, Frederick J. (författare)
- Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England.
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- Meissner, Felix (författare)
- Max Planck Inst Biochem, D-82152 Martinsried, Germany.
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- Herms, Jochen (författare)
- German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.
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- Konnerth, Arthur (författare)
- Tech Univ Munich, Inst Neurosci, D-80802 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany.
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- Marie, Helene (författare)
- Univ Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France.
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- Haass, Christian (författare)
- Univ 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.
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Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany. (creator_code:org_t)
- 2015-08-31
- 2015
- Engelska.
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7573, s. 443-447
- Relaterad länk:
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http://www.nature.co...
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Geriatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Geriatrics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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Willem, Michael
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Tahirovic, Sabin ...
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Busche, Marc Aur ...
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Ovsepian, Saak V ...
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Chafai, Magda
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Kootar, Scheraza ...
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visa fler...
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Hornburg, Daniel
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Evans, Lewis D. ...
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Moore, Steven
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Daria, Anna
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Hampel, Heike
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Mueller, Veronik ...
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Giudici, Camilla
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Nuscher, Brigitt ...
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Wenninger-Weinzi ...
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Kremmer, Elisabe ...
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Heneka, Michael ...
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Thal, Dietmar R.
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Giedraitis, Vilm ...
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Lannfelt, Lars
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Mueller, Ulrike
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Livesey, Frederi ...
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Meissner, Felix
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Herms, Jochen
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Konnerth, Arthur
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Marie, Helene
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Haass, Christian
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Geriatrik
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Neurovetenskaper
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