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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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“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
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“We and others previously reported that MT5-MMP can modulate neuronal activity [8, 9, 12, 13].”
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“Amyloid precursor protein (APP) is another relevant substrate of MT5-MMP [11–13], which holds a central position in Alzheimer’s disease (AD) pathogenesis.”
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
“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
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“In this diagram, adapted from [14], we show that the ANJJ antibody [9,10], which recognizes the free C-terminal neoepitope of sAPPβ (green vertical line) created by BACE1 cleavage of APP carrying the Swedish mutation, will detect Aη-β and sAPPβ (green rectangles) but not sAPPη or Aη-α.”
InfluentialLichtenthaler, S. F., Lemberg, M. K., & Fluhrer, R. (2018) · The EMBO Journal · doi:10.15252/embj.201899456 · Cited by 323
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“In addition to Aβ, other cleavage products of APP, such as the APP intracellular domain, the soluble APP, and eta-amyloid (Aη), might play a role in AD (Müller et al. 2008, 2017; Willem et al. 2015).”
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“The two main pathways by which APP can be processed are the non-amyloidogenic and the amyloidogenic pathways, although more recently an additional pathway has been proposed (Willem et al., 2015).”
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“This is reminiscent of functions attributed to proteolytic cleavage fragments from the amyloid precursor protein (APP) (63, 64).”
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“These concerns were further fueled by recent findings demonstrating that BACE inhibition upregulates non-canonical APP processing and production of Aη fragments that impair neuronal activity and LTP (Willem et al., 2015).”
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Deyts, C., Thinakaran, G., & Parent, A. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.01.005 · Cited by 121
“In addition to the processing pathways described above, APP ectodomain can be cleaved by other secretases as recently described [3,4].”
BackgroundZhu, K., Xiang, X., Filser, S., Marinković, P., Dorostkar, M. M., Crux, S., Neumann, U., Shimshek, D. R., Rammes, G., Haass, C., et al. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.12.023 · Cited by 107
“Overexpression of sAPPα rescued LTP reduction in an AD mouse model (57), whereas application of Aη-α-supplemented media attenuated hippocampal LTP in WT mice (56).”
MethodSelf-citationAliès, B., Conte‐Daban, A., Sayen, S., Collin, F., Kieffer, I., Guillon, E., Faller, P., & Hureau, C. (2016) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.6b01733 · Cited by 108
Coronel, R., Bernabeu-Zornoza, A., Palmer, C., Moreno, M. D. M. M., Zambrano, A., Cano, E., & Liste, I. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0914-2 · Cited by 112
“The possible functions of the peptides produced in this pathway are still not well known, although it has been reported that Aη-α peptide can inhibit neuronal activity in the mouse hippocampus under physiological conditions [28] (Fig.”
Understanding the roles of mutations in the amyloid precursor protein in Alzheimer disease
Hunter, S., & Brayne, C. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.218 · Cited by 94
Yuksel, M., & Tacal, Ö. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172415 · Cited by 99
Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges
Zipfel, P., Rochais, C., Baranger, K., Rivera, S., & Dallemagne, P. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00352 · Cited by 94
Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease
Andersen, O. M., Rudolph, I.-M., & Willnow, T. E. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1615-4 · Cited by 83
Brody, D. L., Jiang, H., Wildburger, N. C., & Esparza, T. J. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-017-0293-3 · Cited by 86
García-González, L., Pilat, D., Baranger, K., & Rivera, S. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00244 · Cited by 88
“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).”
BackgroundInfluentialSynaptic dysfunction in early phases of Alzheimer's Disease
Pelucchi, S., Gardoni, F., Luca, M. D., & Marcello, E. E. (2022) · Handbook of clinical neurology · doi:10.1016/b978-0-12-819410-2.00022-9 · Cited by 95
Chen, J., Wang, J., Yin, B., Pang, L., Wang, W., & Zhu, W. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00348 · Cited by 84
Diverse functions of the prion protein – Does proteolytic processing hold the key?
Linsenmeier, L., Altmeppen, H. C., Wetzel, S., Mohammadi, B., Säftig, P., & Glatzel, M. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.06.022 · Cited by 83
“In their model, AD and prion disease lead to decreased ADAM17 activity and reduced levels of neuroprotective sAPPα and PrPC N1 fragments which then aggravates stress conditions and initiates a vicious circle leading to neuronal death [83].”
BackgroundInfluentialADGC, A. D. N. I., Chapuis, J., Flaig, A., Grenier-Boley, B., Eysert, F., Pottiez, V., Deloison, G., Vandeputte, A., Ayral, A.-M., Mendes, T., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1652-z · Cited by 75
“Recently, new δ- and η-secretase activities have been characterized [1, 26, 28], indicating that additional APP processing pathways may exist and may thus modulate Aβ loads.”
BackgroundFanutza, T., Prete, D. D., Ford, M. J., Castillo, P. E., & D'adamio, L. (2015) · eLife · doi:10.7554/elife.09743 · Cited by 87
“Ah-a can reduce LTP (Willem et al., 2015). b-CTF mediates long-term synaptic plasticity deficits, behavioral deficits and neurodegeneration (Neve et al., 1996, Neve and Robakis, 1998, Oster-Granite et al., 1996, Tamayev et al., 2012b, 2012c).”
BackgroundLudewig, S., & Körte, M. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00161 · Cited by 84
“The diverse functions of the APP protein family during either preor postsynaptically initiated processes of synaptic plasticity and under basal conditions are summarized in Figure 2.”
BackgroundInfluentialδ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities
Zhang, Z., Tian, Y., & Ye, K. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-019-0179-3 · Cited by 81
“Except for α-, β-, and γ-secretase, other proteases have also been identified to cleave APP and regulate its physiological and pathological functions [37, 38].”
BackgroundBergström, P., Agholme, L., Nazir, F. H., Şatır, T. M., Toombs, J., Wellington, H., Strandberg, J., Bontell, T. O., Kvartsberg, H., Holmström, M., et al. (2016) · Scientific Reports · doi:10.1038/srep29200 · Cited by 78
Amyloid, APP, and Electrical Activity of the Brain
Hefter, D., Ludewig, S., Draguhn, A., & Körte, M. (2019) · The Neuroscientist · doi:10.1177/1073858419882619 · Cited by 83
“Recently, a third, novel, η - secretase pathway with yet unclear function has been discovered (Willem and others 2015; Fig.”
BackgroundInfluentialMicroglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
Yang, Y., & Zhang, Z. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00110 · Cited by 76
“Microglial Activation and Immune-Inflammatory Response in AD Development Amyloid-beta (Aβ) deposition, abnormal tau phosphorylation, and synaptic dysfunction are the characteristic pathological changes of AD (Figure 1; Robakis et al., 1987; Baas and Black, 1990; Wang et al., 1996; Klyubin et al., 2005; Shankar et al.,…”
BackgroundEisele, Y. S., & Duyckaerts, C. J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1516-y · Cited by 82
“These fragments can specifically lower neuronal activity and long-term potentiation [130].”
Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research?
Hunter, S., & Brayne, C. (2017) · Journal of Negative Results in BioMedicine · doi:10.1186/s12952-017-0066-3 · Cited by 80
“Additional APP cleavages include β’-cleavage by BACE2 [4], δ- and η-cleavage [5, 6] and cleavage by caspase [7].”
BackgroundEggert, S., Thomas, C., Kins, S., & Hermey, G. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0806-x · Cited by 75
“two peptides of 92 or 108 amino acids in length, designated as Aη-β or Aη-α peptides, respectively [28].”
BackgroundUpdate on Biomarkers For Amyloid Pathology in Alzheimer’s Disease
Ashton, N. J., Schöll, M., Heurling, K., Gkanatsiou, E., Portelius, E., Höglund, K., Brinkmalm, G., Hye, A., Blennow, K., & Zetterberg, H. (2018) · Biomarkers in Medicine · doi:10.2217/bmm-2017-0433 · Cited by 78
“These include N-terminally extended Aβ forms that span the BACE1 cleavage site of APP [103, 136-138] and Aβ forms that extend C-terminally towards the δ- and ε-cleavage sites at amino acids 45, 46, 48 and 49 [139].”
BackgroundDar, N. J., & Glazner, G. W. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03404-x · Cited by 77
Johnson, E. C. B., Ho, K., Yu, G.-Q., Das, M., Sanchez, P. E., Djukic, B., Lopez, I., Yu, X., Gill, M., Zhang, W., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00393-5 · Cited by 73
“It is also worth considering Aη-α fragments in this context, which are derived from APP by η- and αsecretase cleavage and have been shown to impair synaptic and neuronal functions in acute hippocampal slices [148, 149].”
BackgroundInhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease
Yan, R., Fan, Q., Zhou, J., & Vassar, R. J. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.025 · Cited by 71
“, who refer this cleavage as η-secretase, which possesses membrane-bound matrix metalloproteinase activity and cleaves APP695 between residues 504-505 (Willem et al., 2015).”
InfluentialThe Potential Role of Ferroptosis in Alzheimer’s Disease
Zhang, G., Zhang, Y.-R., Shen, Y., Wang, Y., Zhao, M. L., & Sun, L. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201369 · Cited by 71
You, M., Pan, Y., Liu, Y., Chen, Y., Wu, Y., Si, J., Wang, K., & Hu, F. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00428 · Cited by 70
“BACE1 and γ-secretase are needed for the amyloidogenic pathological processing of APP to generate Aβ fragments (Willem et al., 2015).”
BackgroundModulation of γ- and β-secretases as early prevention against Alzheimer's disease
Voytyuk, I., De Strooper, B., & Chávez-Gutiérrez, L. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.001 · Cited by 67
“Furthermore, very little attention is given to the fact that BACE1 inhibition leads to compensatory processing of APP, resulting in p3 fragments (77) and alternative “η-peptides” (78) whose potential contribution to neurodegenerative processes has been hardly investigated.”
Nizari, S., Guo, L., Davis, B. M., Normando, E. M., Galvão, J., Turner, L., Bizrah, M., Dehabadi, M. H., Tian, K., & Cordeiro, M. F. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.397 · Cited by 69
Baranger, K., Giannoni, P., Girard, S. D., Girot, S., Gaven, F., Stephan, D., Migliorati, M., Khrestchatisky, M., Bockaert, J., Marchetti, E., et al. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.031 · Cited by 71
“…involves the sequential proteolytic processing of APP by β-secretase (BACE-1) and the γ-secretase complex, but other recently reported proteolytic systems may also account for the cytotoxic cleavage of APP (Baranger et al., 2016a; Baranger et al., 2016b; Willem et al., 2015; Zhang et al., 2015).”
BackgroundRegulation of AMPA Receptor Trafficking by Protein Ubiquitination
Widagdo, J., Guntupalli, S., Jang, S. E., & Anggono, V. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00347 · Cited by 68
“For example, protein interacting with C-kinase 1 (PICK1), which directly interacts with GluA2/3 subunits and regulates the endosomal recycling of AMPARs (Xia et al., 1999; Citri et al., 2010; Widagdo et al., 2016), is a critical regulator of long-term potentiation (LTP), long-term depression (LTD) and homeostatic syna…”
BackgroundInfluentialLauritzen, I., Pardossi‐Piquard, R., Bourgeois, A., Bécot, A., & Checler, F. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190325092841 · Cited by 68
A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor
Liu, L., Ding, L., Rovere, M., Wolfe, M. S., & Selkoe, D. J. (2019) · Journal of Cell Biology · doi:10.1083/jcb.201806205 · Cited by 64
“After aligning the TMDs of BACE1 and MT5-MMP (the identified η-secretase; Willem et al., 2015; Baranger et al., 2016), we generated a chimeric BACE1 molecule by swapping in the TMD of MT5-MMP (Fig.”
BackgroundMethodResultInfluentialThe amyloid precursor protein: a converging point in Alzheimer’s disease
Delport, A., & Hewer, R. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02863-x · Cited by 66
“Further, an increase in η-fragments also occurs with BACE1 inhibition (β-secretase inhibition), particularly Aη-α [100].”
BackgroundInfluentialSecretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2
Lichtenthaler, S. F., Tschirner, S. K., & Steiner, H. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.09.003 · Cited by 60
Positive Feedback Loops in Alzheimer’s Disease: The Alzheimer’s Feedback Hypothesis
Doig, A. J. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180583 · Cited by 67
“We thus have a vast host of A derivatives, with varying N- and C-termini, aggregated species of different sizes, and oligomers formed from more than one type of peptide, of differing populations, lifetimes, potential interactions with other molecules and toxicities.”
BackgroundHamm, V., Héraud, C., Bott, J.-B., Herbeaux, K., Strittmatter, C., Mathis, C., & Goutagny, R. (2017) · Science Advances · doi:10.1126/sciadv.1601068 · Cited by 68
Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease
Eysert, F., Kinoshita, P. F., Mary, A., Vaillant-Beuchot, L., Checler, F., & Chami, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249521 · Cited by 63
Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
Checler, F., Afram, E., Pardossi‐Piquard, R., & Lauritzen, I. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100489 · Cited by 63
“A recent study also proposed another neuroprotective role of BACE1, since the inhibition of this enzyme was found to enhance the levels of both ƞ-secretase and Aƞα, the latter was proposed to be neurotoxic (27).”
BackgroundHIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration
Chai, Q., Jovasevic, V., Malikov, V., Sabo, Y., Morham, S. G., Walsh, D., & Naghavi, M. H. (2017) · Nature Communications · doi:10.1038/s41467-017-01795-8 · Cited by 60
ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease
Letronne, F., Laumet, G. O., Ayral, A., Chapuis, J., Demiautte, F., Laga, M., Vandenberghe, M. E., Malmanche, N., Leroux, F., Eysert, F., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.06.002 · Cited by 56
Alternative processing of the amyloid precursor protein family by rhomboid protease RHBDL4.
Paschkowsky, S., Hamzé, M., Oestereich, F., & Munter, L. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.753582 · Cited by 58
“In addition, a recent paper described the formation of novel, toxic A fragments derived from larger APP CTFs (46).”
Background
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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