Journal Article

DZNE-2020-04480

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png η-Secretase processing of APP inhibits neuronal activity in the hippocampus.

Willem, M. (Corresponding author) ; Tahirovic, S.DZNE* ; Busche, M. A. ; Ovsepian, S. V.DZNE* ; Chafai, M. ; Kootar, S. ; Hornburg, D. ; Evans, L. D. B. ; Moore, S. ; Daria, A. ; Hampel, H. ; Müller, V. ; Giudici, C. ; Nuscher, B. ; Wenninger-Weinzierl, A.DZNE* ; Kremmer, E.DZNE* ; Heneka, M. T.DZNE* ; Thal, D. R. ; Giedraitis, V. ; Lannfelt, L. ; Müller, U. ; Livesey, F. J. ; Meissner, F. ; Herms, J.DZNE* ; Konnerth, A. ; Marie, H. ; Haass, C. (Last author)DZNE*

2015
Nature Publ. Group65848 London [u.a.]

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Please use a persistent id in citations: doi:10.1038/nature14864

Abstract: Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. 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, 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.

Keyword(s): ADAM Proteins: metabolism (MeSH) ; ADAM10 Protein (MeSH) ; Alzheimer Disease: enzymology (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Amyloid Precursor Protein Secretases: antagonists & inhibitors (MeSH) ; Amyloid Precursor Protein Secretases: cerebrospinal fluid (MeSH) ; Amyloid Precursor Protein Secretases: deficiency (MeSH) ; Amyloid Precursor Protein Secretases: genetics (MeSH) ; Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Amyloid beta-Protein Precursor: cerebrospinal fluid (MeSH) ; Amyloid beta-Protein Precursor: chemistry (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Animals (MeSH) ; Aspartic Acid Endopeptidases: antagonists & inhibitors (MeSH) ; Aspartic Acid Endopeptidases: deficiency (MeSH) ; Aspartic Acid Endopeptidases: genetics (MeSH) ; Aspartic Acid Endopeptidases: metabolism (MeSH) ; Calcium Signaling (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Hippocampus: cytology (MeSH) ; Hippocampus: enzymology (MeSH) ; Hippocampus: physiology (MeSH) ; Humans (MeSH) ; In Vitro Techniques (MeSH) ; Long-Term Potentiation (MeSH) ; Male (MeSH) ; Matrix Metalloproteinases, Membrane-Associated: deficiency (MeSH) ; Matrix Metalloproteinases, Membrane-Associated: metabolism (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Mice (MeSH) ; Molecular Weight (MeSH) ; Neurites: enzymology (MeSH) ; Neurites: metabolism (MeSH) ; Neurons: enzymology (MeSH) ; Neurons: physiology (MeSH) ; Peptide Fragments: chemistry (MeSH) ; Peptide Fragments: metabolism (MeSH) ; Plaque, Amyloid (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Proteolysis (MeSH) ; Single-Cell Analysis (MeSH) ; APP protein, human ; Amyloid beta-Protein Precursor ; Membrane Proteins ; Peptide Fragments ; Amyloid Precursor Protein Secretases ; Aspartic Acid Endopeptidases ; BACE1 protein, human ; Bace1 protein, mouse ; ADAM Proteins ; Matrix Metalloproteinases, Membrane-Associated ; Mmp24 protein, mouse ; ADAM10 Protein ; ADAM10 protein, human

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Contributing Institute(s):

1. Ex vivo models (AG Tahirovic)
2. Translational Brain Research (AG Herms)
3. ALS, FTLD and Zebrafish models (AG Haass old)
4. Ext HZM (Ext HZM)
5. Neuroinflammation, Biomarker (AG Heneka2)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2015

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; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 40 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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