Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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

Nature. 2015 Oct 15;526(7573):443-7

Authors/Editors: Michael Willem
Sabina Tahirovic
Marc Aurel Busche
Saak V. Ovsepian
Magda Chafai
Scherazad Kootar
Daniel Hornburg
Lewis D. B. Evans
Steven Moore
Anna Daria
Heike Hampel
Veronika Müller
Camilla Giudici
Brigitte Nuscher
Andrea Wenninger-Weinzierl
Elisabeth Kremmer
Michael T. Heneka
Dietmar R. Thal
Vilmantas Giedraitis
Lars Lannfelt
Ulrike Müller
Frederick J. Livesey
Felix Meissner
Jochen Herms
Arthur Konnerth
Hélène Marie
Christian Haass
Publication Date: 2015
Type of Publication: Journal Article

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 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, longterm 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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