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eta-Secretase processing of APP inhibits neuronal activity in the hippocampus
Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany..
German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany..
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..
German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany..
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2015 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7573, p. 443-447Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 526, no 7573, p. 443-447
National Category
Geriatrics Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-265812DOI: 10.1038/nature14864ISI: 000362730200054PubMedID: 26322584OAI: oai:DiVA.org:uu-265812DiVA, id: diva2:866688
Funder
EU, European Research Council, 321366-AmyloidEU, European Research Council, 318987German Research Foundation (DFG), MU 1457/9-1German Research Foundation (DFG), MU 1457/9-2
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-01-10Bibliographically approved

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Giedraitis, VilmantasLannfelt, Lars

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