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η-Secretase processing of APP inhibits neuronal activity in the hippocampus
Open accessAbstract
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.
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“Alternatively to canonical APP processing, MT5-MMP has been shown to cleave APP and to generate an η-CTF from which subsequent processing by α-secretase releases an Aη-α fragment that inhibits LTP in cellulo [12].”
From MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer’s disease (2022) · cites this paper as [12]
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In the citing paper
“Willem and collaborators identified by mass spectrometry the VLAN504-M505ISEPR (APP695 numbering) as a cleavage site for MT5-MMP on APP, which was named η-cleavage site (Willem et al., 2015).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Willem et al., 2015
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“We and others previously reported that MT5-MMP can modulate neuronal activity [8, 9, 12, 13].”
In the citing paper
“Although inhibition of β-secretase activity is predicted to reduce Aβ production, BACE1 inhibitors were seen to increase cleavage of APP by other secretases, thereby enhancing the production of pathogenic APP metabolites [36].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [36]
In the citing paper
“Although the exact nature of sAPP95 produced upon MT1-MMP and MT5-MMP expression needs to be established, it likely corresponds to what was defined as sAPPη by others (Willem et al., 2015).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Willem et al., 2015
In the citing paper
“Aη-α and Aη-β peptides were both detected in human cerebrospinal fluid (CSF) of healthy and AD patients, but no differences in their levels were observed between groups (Willem et al., 2015).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Willem et al., 2015
In the citing paper
“Intriguingly, the Willem’s study did not identify MT1-MMP as cleaving at this VLAN504-M505ISEPR/η-site and it was concluded that only MT5-MMP could act as a η-secretase in vivo (Willem et al., 2015).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Willem et al., 2015
In the citing paper
“In addition, the inhibition of ADAM10 promoted the concerted action of MT5-MMP and BACE-1 to release a shorter peptide, Aη-β, unexpectedly innocuous (Willem et al., 2015).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Willem et al., 2015
In the citing paper
“Amyloid precursor protein (APP) is another relevant substrate of MT5-MMP [11–13], which holds a central position in Alzheimer’s disease (AD) pathogenesis.”
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- Radde, R. et al. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7, 940–946 (2006) · DOI · Paper page
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“η-secretase-mediated APP cleavage releases a soluble APPη ectodomain and retains a membrane bound η-CTF product [36].”
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Metadata
- Authors
- Willem, M., Tahirovic, S., Busche, M. A., Ovsepian, S. V., 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., Kremmer, E., Heneka, M. T., Thal, D. R., Giedraitis, V., Lannfelt, L., Müller, U., Livesey, F. J., Meissner, F., Herms, J., Konnerth, A., Marie, H., & Haass, C.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Munich Cluster for Systems Neurology (DE)
- German Center for Neurodegenerative Diseases (DE)
- Centre National de la Recherche Scientifique (FR)
- Max Planck Institute of Biochemistry (DE)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Bonn (DE)
- Universität Ulm (DE)
- Uppsala University (SE)
- Heidelberg University (DE)
- Corresponding author
- Willem, Michael
- Haass, Christian
- ORCID
- Busche, Marc Aurel
- Ovsepian, Saak V.
- Kootar, Scherazad
- Hornburg, Daniel
- Evans, Lewis D. B.
- Nuscher, Brigitte
- Wenninger-Weinzierl, Andrea
- Heneka, Michael T.
- Thal, Dietmar R.
- Giedraitis, Vilmantas
- Lannfelt, Lars
- Müller, Ulrike
- Livesey, Frederick J.
- Meissner, Felix
- Herms, Jochen
- Konnerth, Arthur
- Marie, Hélène
- Haass, Christian
- Venue
- Nature
- Published
- 2015-08-31
- Volume
- 526
- Issue
- 7573
- Pages
- 443-447
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6570618
- OpenAlex
- W1779570864
- Cited by
- 398
- References
- 71
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 20 · 2023: 23 · 2022: 23 · 2021: 36 · 2020: 46 · 2019: 54 · 2018: 39 · 2017: 58 · 2016: 46 · 2015: 9
- FWCI
- 37.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Site cant be reached (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Lirias (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- DZNE Pub (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Wellcome Trust (101052, 101052/Z/13/Z, 092096)
- European Commission
- Deutsche Forschungsgemeinschaft (MU 1457/9–1)
- Agence Nationale de la Recherche (ANR-11-LABX-0028)
- Eberhard Karls Universität Tübingen
- Universitat de València
- Centre National de la Recherche Scientifique (ANR-11-LABX-0028-01)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Hans und Klementia Langmatz Stiftung
- Medical Research Council (MR/L023784/2, MR/L023784/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APP processing, amyloid precursor protein, ADAM10, BACE1, CTF, long-term potentiation, hippocampus, Alzheimer's disease, amyloid-beta, BACE1 inhibitors, dystrophic neurites, C-terminal fragment
- MeSH terms
- ADAM10 Protein, Alzheimer Disease, Animals, Disease Models, Animal, Female, Hippocampus, Humans, Male, Membrane Proteins, Molecular Weight, Neurons, Peptide Fragments, Protein Processing, Post-Translational, Aspartic Acid Endopeptidases, Neurites, Amyloid beta-Protein Precursor, Long-Term Potentiation, Calcium Signaling, Mice, ADAM Proteins, Matrix Metalloproteinases, Membrane-Associated, Amyloid Precursor Protein Secretases, Plaque, Amyloid, Single-Cell Analysis, Proteolysis, In Vitro Techniques
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