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

Willem, M., Tahirovic, S., Busche, M. A., Ovsepian, S. V., Chafai, M., Kootar, S., et al. (2015). η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature, 526(7573), 443-447. doi:10.1038/nature14864.

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 Creators:
Willem, Michael, Author
Tahirovic, Sabina, Author
Busche, Marc Aurel, Author
Ovsepian, Saak V., Author
Chafai, Magda, Author
Kootar, Scherazad, Author
Hornburg, Daniel1, Author              
Evans, Lewis D. B., Author
Moore, Steven, Author
Daria, Anna, Author
Hampel, Heike, Author
Müller, Veronika, Author
Giudici, Camilla, Author
Nuscher, Brigitte, Author
Wenninger-Weinzierl, Andrea, Author
Kremmer, Elisabeth, Author
Heneka, Michael T., Author
Thal, Dietmar R., Author
Giedraitis, Vilmantas, Author
Lannfelt, Lars, Author
Müller, Ulrike, AuthorLivesey, Frederick J., AuthorMeissner, Felix2, Author              Herms, Jochen, AuthorKonnerth, Arthur, AuthorMarie, Hélène, AuthorHaass, Christian, Author more..
Affiliations:
1Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
2Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society, ou_2149678              

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 Abstract: Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide1. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo2. 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.

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Language(s): eng - English
 Dates: 2015-08-312015-10-15
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/nature14864
 Degree: -

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 526 (7573) Sequence Number: - Start / End Page: 443 - 447 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238