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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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In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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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Citations
Cites
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Age‐dependent NMDA receptor function is regulated by the amyloid precursor protein
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“For APP, APP-CTFs and AICD analysis, optimal conditions for low molecular mass proteins separation were used, as described in (Willem et al., 2015).”
MethodSelf-citationSoluble APP functions as a vascular niche signal that controls adult neural stem cell number
Sato, Y., Uchida, Y., Hu, J., Young‐Pearse, T. L., Niikura, T., & Mukouyama, Y. (2017) · Development · doi:10.1242/dev.143370 · Cited by 22
“Among different fragments of sAPP (Caille et al., 2004; Ohsawa et al., 1999; Olsen et al., 2014; Willem et al., 2015), the soluble Nterminal fragment (aa 18-286) and the 770 aa form sAPP(770) negatively regulate NSC growth but do not affect the number of neurospheres in the culture from acutely dissociated SVZ cells (…”
BackgroundBoguszewska‐Czubara, A., Budzyńska, B., Skalicka‐Woźniak, K., & Kurzepa, J. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180514111500 · Cited by 22
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Brzdąk, P., Nowak, D., Wiera, G., & Mozrzymas, J. W. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00178 · Cited by 21
“Additionally, a recent study found that MT5-MMP and soluble MMPs contributed to η-secretase activity (Willem et al., 2015).”
BackgroundInfluentialOrdered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway
Maity, B. K., Das, A. K., Dey, S., Moorthi, U. K., Kaur, A., Dey, A., Surendran, D., Pandit, R., Kallianpur, M., Chandra, B., et al. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00015 · Cited by 20
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Self-citationMichno, W., Blennow, K., Zetterberg, H., & Brinkmalm, G. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15466 · Cited by 18
Amyloidogenesis: What Do We Know So Far?
Alraawi, Z., Banerjee, N., Mohanty, S., & Kumar, T. K. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213970 · Cited by 22
Krämer, L. M., Brettschneider, J., Lennerz, J. K., Walcher, D., Fang, L., Rosenbohm, A., Balakrishnan, K., Benckendorff, J., Möller, P., Just, S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-34808-7 · Cited by 19
Self-citationVrancx, C., & Annaert, W. G. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.05.007 · Cited by 18
“Alternatively, the metalloprotease MT5-MMP generates APP-η CTFs that in turn become substrates for α - or β -secretase; the resulting A η - α and A η - β peptides are suggested to also disrupt neuronal health [25], possibly by modulating NMDA receptor activity [26].”
Parkin as a Molecular Bridge Linking Alzheimer’s and Parkinson’s Diseases?
Checler, F., & da Costa, C. A. (2022) · Biomolecules · doi:10.3390/biom12040559 · Cited by 19
Navarro‐Hortal, M. D., Romero‐Márquez, J. M., Osta, S., Jiménez-Trigo, V., Muñoz-Ollero, P., & Varela‐López, A. (2022) · Diseases · doi:10.3390/diseases10020028 · Cited by 18
“It has been suggested that Aβ would activate tau protein kinase 1β, leading to the abnormal phosphorylation of tau protein and the promotion of the formation of paired helical filaments and NFTs, which accelerate the development of tau pathology [28,29,61].”
BackgroundChung, J., Phukan, G., Vergote, D., Mohamed, A., Maulik, M., Stahn, M., Andrew, R. J., Thinakaran, G., Chaves, E., & Kar, S. (2018) · Molecular and Cellular Biology · doi:10.1128/mcb.00529-17 · Cited by 19
An inorganic overview of natural Aβ fragments: Copper(II) and zinc(II)-mediated pathways
Lanza, V., Bellia, F., & Rizzarelli, E. (2018) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2018.04.004 · Cited by 18
Secreted APP Modulates Synaptic Activity: A Novel Target for Therapeutic Intervention?
Haass, C., & Willem, M. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.058 · Cited by 18
Self-citationJin, Z., Lu, Y., Tang, H., & Cui, H. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70472 · Cited by 24
“15 Pathologically, APP is sequentially cleaved by β -secretase and γ -secretase, releasing the amyloid-beta (A β ) peptide.”
AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP / PS1 mice
Wen, Q., Luo, B., Xie, X., Zhou, G., Chen, J., Li, S., Liu, Y., Xie, S., Chen, L., Li, K., et al. (2022) · Traffic · doi:10.1111/tra.12874 · Cited by 19
Luo, M., Pang, Y., Li, J., Yi, L., Wu, B., Tian, Q., He, Y., Wang, M., Xia, L., He, G., et al. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.10.015 · Cited by 17
Peptide-based inhibitors and nanoparticles: Emerging therapeutics for Alzheimer’s disease
Mojarad-Jabali, S., & Roh, K. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.125055 · Cited by 17
Consecutive Analysis of BACE1 Function on Developing and Developed Neuronal Cells
Kamikubo, Y., Takasugi, N., Niisato, K., Hashimoto, Y., & Sakurai, T. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160806 · Cited by 17
“In addition, recent studies showed that A (cid:2) PP is processed by other proteases, δ - and η - secretase, and its products inhibit neural activity and memory [41, 42].”
Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes
Yang, H., Wang, Y., & Kar, S. (2017) · Glia · doi:10.1002/glia.23191 · Cited by 17
“Some recent studies have shown that the APP holoprotein can be processed in neuronal cells by a novel h-secretase pathway generating h-CTF (Willem et al., 2015).”
BackgroundInfluentialSchaduangrat, N., Prachayasittikul, V., Choomwattana, S., Wongchitrat, P., Phopin, K., Suwanjang, W., Malik, A. A., Vincent, B., & Nantasenamat, C. (2019) · Medicinal Research Reviews · doi:10.1002/med.21563 · Cited by 17
García‐González, L., Paumier, J., Louis, L., Pilat, D., Bernard, A., Stephan, D., Jullien, N., Checler, F., Nivet, E., Khrestchatisky, M., et al. (2021) · The FASEB Journal · doi:10.1096/fj.202100593r · Cited by 16
van Maanen, E. M. T., van Steeg, T. J., Ahsman, M. J., Michener, M. S., Savage, M. J., Kennedy, M. E., Kleijn, H. J., Stone, J. A., & Danhof, M. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.244699 · Cited by 17
“The specific enzyme-linked immunosorbent assays used for the concentrationmeasurementswere described previously (Sankaranarayanan et al., 2009; Wu et al., 2011).”
MethodSatarker, S., Gurram, P. C., Nassar, A., Manandhar, S., Vibhavari, R. J. A., Yarlagadda, D. L., Mudgal, J., Lewis, S. A., Arora, D. S., & Nampoothiri, M. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03844-4 · Cited by 16
“The Aβ cascade hypothesis involves the mechanisms of β-secretase and γ-secretase-mediated formation and accumulation of Aβ from amyloid precursor protein (APP) [4], including the η-secretases as well [5].”
BackgroundAPP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors
Dunot, J., Moréno, S., Gandin, C., Pousinha, P. A., Amici, M., Dupuis, J. P., Anisimova, M., Winschel, A., Uriot, M., Petshow, S., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.05.027 · Cited by 16
Self-citationde Weerd, L., Hummel, S., Müller, S. A., Paris, I., Sandmann, T., Eichholtz, M., Gröger, R., Englert, A. L., Wagner, S., Ha, C., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00878-1 · Cited by 18
Self-citationHaytural, H., Lundgren, J. L., Köse, T. B., Jordá-Siquier, T., Kalcheva, M., Ahmed, M. S., Winblad, B., Sundström, E., Barthet, G., Tjernberg, L., et al. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00273 · Cited by 11
“The situation is further complicated by the fact that also CTFβ and the fragment derived from sequential cleavage by η- and α-secretase (Aη-α) have been shown to be neurotoxic and may therefore be involved in the pathology of AD (Oster-Granite et al., 1996; McPhie et al., 1997; Bittner et al., 2009; Jiang et al., 2010…”
BackgroundInfluentialEarly Dendritic Dystrophy in Human Brains With Primary Age-Related Tauopathy
Shi, Y., Tu, T., Jiang, J., Zhang, Q., Ai, J.-Q., Pan, A., Manavis, J., Tu, E., & Yan, X. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.596894 · Cited by 14
“, 2016), and γ- and η-secretase components (Su et al., 1993; Willem et al., 2015), thereby likely serving as an important origin of the plaque-forming Aβ.”
BackgroundVarshavskaya, K. B., Mitkevich, V. A., Makarov, A. А., & Barykin, E. P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315036 · Cited by 18
Genetic and environmental risk factors for dementia in African adults: A systematic review
Donkor, D. M., Marfo, E., Bockarie, A. S., Tettevi, E. J., Antwi, M. H., Dogah, J., Osei, G. N., & Simpong, D. L. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70220 · Cited by 15
“90”
Amyloid precursor protein 770 is specifically expressed and released from platelets
Miura, S., Yoshihisa, A., Misaka, T., Yamaki, T., Kojima, T., Toyokawa, M., Ogawa, K., Shimura, H., Yamamoto, N., Kasahara, K., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.012904 · Cited by 15
“To analyze the proteolytic cleavage of platelet APP following stimulation in more detail, we performed Western blotting analysis using anti–N-terminal APP antibody 22C11 and anti–C-terminal APP antibody (which detects the C-terminal fragments (CTFs) of APP) (26).”
MethodSolid‐Phase Synthesis and Characterization of N‐Terminally Elongated Aβ −3– x ‐Peptides
Beyer, I., Rezaei‐Ghaleh, N., Klafki, H., Jahn, O., Haußmann, U., Wiltfang, J., Zweckstetter, M., & Knölker, H. (2016) · Chemistry - A European Journal · doi:10.1002/chem.201600892 · Cited by 15
Chiang, A. C. A., Fowler, S., Reddy, R., Pletniková, O., Troncoso, J. C., Sherman, M. A., Lesné, S., & Jankowsky, J. L. (2017) · American Journal Of Pathology · doi:10.1016/j.ajpath.2017.11.011 · Cited by 17
Hornburg, D., Kruse, T., Anderl, F., Daschkin, C., Semper, R. P., Klar, K., Guenther, A., Mejías‐Luque, R., Schneiderhan‐Marra, N., Mann, M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-53493-8 · Cited by 14
Self-citationTok, S., Maurin, H., Delay, C., Crauwels, D., Manyakov, N. V., der Elst, W. V., Moechars, D., & Drinkenburg, W. H. I. M. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01393-w · Cited by 14
“However, in addition to increases in Aβ40 and Aβ42, other cleavage products such as the APP intracellular domain (AICD), C-terminal fragment α/β, soluble APP α/β, p3[9], and Aη [10], are some of the other currently identified cleavage products likely to increase as APP expression levels also increase.”
BackgroundLiu, Y., Zhao, H., Li, Q., Cui, H.-W., & Huang, G. (2022) · Aging and Disease · doi:10.14336/ad.2022.1211 · Cited by 15
“secretase (BACE-1) cleaves APP to generate the C99 fragment (also known as APP CTF-β), which comprises the N-terminus of Aβ [30].”
BackgroundMolecular mechanism of secreted amyloid-β precursor protein in binding and modulating GABA B R1a
Feng, M., Song, Y., Chen, S. H., Zhang, Y., & Zhou, R. (2021) · Chemical Science · doi:10.1039/d0sc06946a · Cited by 13
Vnencak, M., Schölvinck, M. L., Schwarzacher, S. W., Deller, T., Willem, M., & Jedlička, P. (2019) · Brain Structure and Function · doi:10.1007/s00429-019-01836-6 · Cited by 13
Self-citationThe β-Secretase Substrate Seizure 6–Like Protein (SEZ6L) Controls Motor Functions in Mice
Ong-Pålsson, E., Njavro, J. R., Wilson, Y. M., Pigoni, M., Schmidt, A., Müller, S. A., Meyer, M., Hartmann, J., Busche, M. A., Gunnersen, J. M., et al. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02660-y · Cited by 14
Self-citationAow, J., Huang, T.-R., Goh, Y. T., Sun, A. X., Thinakaran, G., & Koo, E. H. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112774 · Cited by 12
Wirths, O., Lehnen, C., Fricke, M., Talucci, I., Klafki, H., Morgado, B., Lehmann, S., Münch, C., Liepold, T., Wiltfang, J., et al. (2024) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12991 · Cited by 14
“…the same staining pattern with decorated dystrophic neurites has previously been described for antibodies detecting A η epitopes, which are located close to the A β peptide sequence in APP [49] and which seem to be generated in part by MT5-MMP, a membrane-bound matrix metalloproteinase [50].”
BackgroundSecretase promotes AD progression: simultaneously cleave Notch and APP
Yang, K.-F., Zhang, J., Feng, M., Yao, K., Liu, Y.-Y., Zhou, M.-S., & Jia, H. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1445470 · Cited by 13
Porphyromonas gingivalis Impairs Microglial Aβ Clearance in a Mouse Model
Xie, M., Huang, X., Tang, Q., Yu, S., Zhang, K., Lu, X., Zhang, Y., Wang, J., Zhang, L., & Chen, L. (2025) · Journal of Dental Research · doi:10.1177/00220345241294009 · Cited by 12
“Therefore, we analyzed APP expression in the brains of APP/ PS1 mice by Western blot as in previous studies (Willem et al. 2015; Van Gool et al. 2019).”
Matrix metalloproteinase 13, a new target for therapy in Alzheimer's disease
Paumier, J., & Thinakaran, G. (2019) · Genes & Diseases · doi:10.1016/j.gendis.2019.02.004 · Cited by 12
Modulators of Amyloid β-Protein (Aβ) Self-Assembly
Rahimi, F., Li, H. J., Sinha, S., & Bitan, G. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00006-x · Cited by 12
“…β-Secretase inhibitors are currently being tested in several clinical trials (Vassar, 2014), yet recent research showing that these inhibitors may lead to accumulation of N-terminally extended APP fragments with substantial neurotoxicity are worrisome (Kaneko et al., 2014; Willem et al., 2015).”
BackgroundLlorente, P., Martins, S., Sastre, I., Aldudo, J., Recuero, M., Adjaye, J., & Bullido, M. J. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5917187 · Cited by 10
“According to the literature, this fragment is compatible with the action of noncanonical secretases, particularly MMP14, MMP24, and AEP [7, 8, 18].”
BackgroundEx vivo analysis platforms for monitoring amyloid precursor protein cleavage
Kamikubo, Y., Jin, H., Zhou, Y., Niisato, K., Hashimoto, Y., Takasugi, N., & Sakurai, T. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1068990 · Cited by 11
“On the other hand, APP cleavage products other than Aβ have been reported to be neurotoxic or neuroprotective (Chasseigneaux and Allinquant, 2012; Willem et al., 2015; Kaneshiro et al., 2022).”
BackgroundJean-Louis, T. L., Rockwell, P., & Figueiredo‐Pereira, M. E. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.10.009 · Cited by 11
“A recent study reported that dystrophic neurites in AD brains are particularly enriched in CTF-APP fragments generated by at least three of the secretases, α, β and η (Willem et al., 2015).”
BackgroundStudies of the Process of Amyloid Formation by Aβ Peptide
Galzitskaya, O. V., Galushko, E. I., & Selivanova, O. M. (2018) · Biochemistry (Moscow) · doi:10.1134/s0006297918140079 · Cited by 11
“In addition, there is η-secretase, which forms amyloid-η fragments that inhibit neuronal functions [43].”
BackgroundWard, J. F., Wang, H., Saunders, A. J., Tanzi, R. E., & Zhang, C. M. (2017) · PubMed · Cited by 11
Re-Arranging the Puzzle between the Amyloid-Beta and Tau Pathology: An APP-Centric Approach
Haut, F., Argyrousi, E. K., & Arancio, O. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010259 · Cited by 11
“Interestingly, A η - α was shown to impair synaptic plasticity in hippocampal slices ex vivo and to reduce neuronal activity in vivo, while A η - β fragments have no effects in these measurements [16].”
BackgroundCross-Linked Amyloid β-Protein Oligomers: A Missing Link in Alzheimer’s Disease Pathology?
Urbanc, B. (2021) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.0c07716 · Cited by 11
Lana, E., Gellerbring, A., Jung, S., Nordberg, A. K., Lithner, C. U., & Darreh‐Shori, T. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00176 · Cited by 10
Eta-secretase-like processing of the amyloid precursor protein (APP) by the rhomboid protease RHBDL4
Penalva, Y. C. M., Paschkowsky, S., Recinto, S. J., Duchesne, A., Hammond, T., Spiegler, P., Jansen, G., Levet, C., Charron, F. M., Freeman, M., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107541 · Cited by 9
“Intriguingly, a previous fi nding by Willem et al. sparked interest in a novel (cid:1) 8 to 14 kDa APP fragment subsequently named A h (18).”
InfluentialChauhan, P., Wadhwa, K., & Singh, G. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.156109 · Cited by 12
Yazdi, M. K., Alavi, M. S., & Roohbakhsh, A. (2024) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13981 · Cited by 11
Shaban, H., O’Connor, R., Ovsepian, S. V., Dinan, T. G., Cryan, J. F., & Schellekens, H. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.09.003 · Cited by 9
Self-citationTMP21 in Alzheimer’s Disease: Molecular Mechanisms and a Potential Target
Qiu, K., Zhang, X., Wang, S., Li, C., Wang, X., Li, X., & Wu, Y. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00328 · Cited by 10
RNA Isoform Diversity in Human Neurodegenerative Diseases
Liu, C. S., Park, C. Y., Ngo, T., Saikumar, J., Palmer, C. R., Shahnaee, A., Romanow, W. J., & Chun, J. J. M. (2024) · eNeuro · doi:10.1523/eneuro.0296-24.2024 · Cited by 8
“The absence of the N terminus may prevent the generation of soluble APP that inhibits β -secretase (Obregon et al., 2012; Peters-Libeu et al., 2015; Willem et al., 2015), and therefore the samples expressing these NNC isoforms may potentially lack a protective mechanism limiting amyloid-β plaque…”
"APP"reciating the complexity of HIV-induced neurodegenerative diseases
Naghavi, M. H. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1007309 · Cited by 8
Chami, M., & Checler, F. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200225102941 · Cited by 8
Arnst, N., Mairal, P. B., García‐González, L., Arnaud, L., Greetham, L., Nivet, E., Rivera, S., & Dityatev, A. E. (2021) · Cells · doi:10.3390/cells10071705 · Cited by 8
Molavipordanjani, S., Emami, S., & Hosseinimehr, S. J. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180410104023 · Cited by 10
Piłat, D., Paumier, J., Louis, L., Manrique, C., García‐González, L., Stephan, D., Bernard, A., Pardossi‐Piquard, R., Checler, F., Khrestchatisky, M., et al. (2024) · Biomolecules · doi:10.3390/biom14121645 · Cited by 7
“Moreover, β - and α -secretase cleavage of η -CTF may also generate N-terminally elongated A β species, i.e., A η - β and A η - α [21], which impair long-term potentiation (LTP) [22].”
Fan, J., Wei, X., Dong, H. Y., Zhang, Y., Zhou, Y., Xu, M., & Xiao, G. (2022) · Critical Reviews in Analytical Chemistry · doi:10.1080/10408347.2022.2132812 · Cited by 7
PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation
Xu, M., Li, J., Xia, L., Du, Y., Wu, B., Shi, X., Tian, N., Pang, Y., Yi, L., Chen, M., et al. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114688 · Cited by 8
Ankul Singh, S., Ansari, M. N., Elossaily, G. M., Vellapandian, C., & Prajapati, B. G. (2024) · ACS Omega · doi:10.1021/acsomega.3c06328 · Cited by 7
Mechanismen der Alzheimer-Krankheit
Busche, M. A., Staufenbiel, M., Willem, M., Haass, C., & Förstl, H. (2016) · Der Nervenarzt · doi:10.1007/s00115-015-0041-5 · Cited by 7
Self-citationLoss of the APP regulator RHBDL4 preserves memory in an Alzheimer’s disease mouse model
Penalva, Y. C. M., Paschkowsky, S., Yang, J., Recinto, S. J., Cinkornpumin, J. K., Ruelas, M., Xiao, B., Nitu, A., Kwon, S. Y., Wu, H. Y.-L., et al. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07579-z · Cited by 6
“Speci fi cally, we found that RHBDL4 knockout (R4 − / − ) mixed cortical cultures did not produce a RHBDL4-speci fi c APP fragment termed “ A η -like ” for its resemblance to the APP fragment originally described to be produced by MT5-MPP by Willem et al. [23, 24].”
Vasques, J. F., Heringer, P. V. B., Gonçalves, R. G. D. J., Campello‐Costa, P., Serfaty, C. A., & Faria‐Melibeu, A. D. C. (2017) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2017.03.003 · Cited by 6
Ovsepian, S. V., Horáček, J., O’Leary, V. B., & Höschl, C. (2020) · The Neuroscientist · doi:10.1177/1073858420940943 · Cited by 8
Self-citationEarly involvement of D-serine in β-amyloid-dependent pathophysiology
Billard, J., Ploux, E., Largillière, S., Corvaisier, S., Gorisse-Hussonnois, L., Radzishevsky, I. S., Wolosker, H., & Fréret, T. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05691-z · Cited by 5
Hunter, S., Walsh, S., & Brayne, C. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03156-0 · Cited by 7
“Other cleavages, e.g. by BACE2 [129] and the N-terminal eta-cleavage [130], have been omitted here for clarity but must be included in the full APP matrix approach.”
Cerebral amyloid angiopathy-related cardiac injury: Focus on cardiac cell death
Xu, X., Xu, H., & Zhang, Z. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1156970 · Cited by 6
“δ and η secreting enzymes can cleave APP to produce two prominent fragments, sAPPδ and sAPPη (Willem et al., 2015; Zhang et al., 2015).”
BackgroundNew tricks from an old dog: Another synaptotoxic fragment from APP
Tyan, S.-H., & Koo, E. H. (2015) · Cell Research · doi:10.1038/cr.2015.125 · Cited by 5
Can brain impermeable BACE1 inhibitors serve as anti-CAA medicine?
Li, J., Huang, L., Liu, F., Tang, B., & Yan, X. (2017) · BMC Neurology · doi:10.1186/s12883-017-0942-y · Cited by 5
Jang, J.-Y., Rhim, H., & Kang, S. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.10.014 · Cited by 5
The Amyloid Precursor Protein: More than Just Amyloid- Beta
Jevtic, S. D., & Provias, J. (2019) · Journal of Neurology and Experimental Neuroscience · doi:10.17756/jnen.2019-045 · Cited by 5
“Mediated by MT5-MMP (membrane-type 5-matrix metalloproteinase) [30, 31].”
BackgroundYang, C., Bonelli, S., Calligaris, M., Carreca, A. P., Müller, S. A., Lichtenthaler, S. F., Troeberg, L., & Scilabra, S. D. (2022) · Membranes · doi:10.3390/membranes12060578 · Cited by 5
Cappai, R. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13546 · Cited by 4
“Moreover, Ab heterogeneity remains just as topical today as a recent study described a novel N-terminal processing pathway of APP that yielded an N-terminally elongated, but C-terminally truncated Ab peptide (Willem et al. 2015).”
BackgroundAPP β-CTF triggers cell-autonomous synaptic toxicity independent of AβPreprint
Luo, M., Zhou, J., Sun, C., Chen, W., Fu, C., Si, C., Zhang, Y., Geng, Y., & Chen, Y. (2024) · eLife · doi:10.7554/elife.100968 · Cited by 5
Ahammad, R. U., Spencer, B. J., Quach, B., Salehi, S. N., & Rissman, R. A. (2025) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.70117 · Cited by 4
Li, S., Xiao, D., Yusufu, R., Huang, F., Feng, Y., Abudureyimu, A., Zhao, J., Jiang, H., & Wei, F. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.158299 · Cited by 6
Wang, H., Lakshmana, M. K., & Fields, G. (2024) · Journal of Cellular Physiology · doi:10.1002/jcp.31218 · Cited by 4
“Although recombinantly expressed A η ‐ β was initially reported to not lower hippocampal long ‐ term potentiation nor suppress the activity of hippocampal neurons (Willem et al., 2015), it was subsequently reported by the same researchers that chemically synthesized A η ‐ β impaired hippocampal long ‐ term potentiatio…”
BackgroundResultInfluentialA synapse perspective on the function of the amyloid precursor protein
Kruse, P., Eichler, A., Klukas, L., & Lenz, M. (2025) · Science Progress · doi:10.1177/00368504251360728 · Cited by 5
Huo, Q., Tabassum, S., Chen, M., Sun, M., Deng, Y., Zheng, X., Li, Y., Chen, J., Long, C., & Yang, L. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201557 · Cited by 4
A short peptide from sAPPα binding to BACE1-APP action site rescues Alzheimer-like pathology
Lai, X., Hu, J., Liu, H., Lan, L., Long, Y., Gao, X., & Deng, J. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.136397 · Cited by 5
de Farias, A. R. M., Pelletier, A., Iohan, L. D. C. C., Saha, O., Bonnefond, A., Amouyel, P., Delahaye, F., Lambert, J., & Costa, M. R. (2023) · Biomedicines · doi:10.3390/biomedicines11092564 · Cited by 4
An Insight into the Protein Aggregation in Alzheimer’s Disease and its Inhibition
Khan, A. B., & Khan, R. H. (2023) · Protein and Peptide Letters · doi:10.2174/0109298665247757231020044633 · Cited by 4
López‐Font, I., Boix, C. P., Zetterberg, H., Blennow, K., & Sáez‐Valero, J. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161275 · Cited by 4
“All the canonical and non-canonical extracellular N-terminal A (cid:2) PP fragments are present in human CSF [11, 34–38] and thus, other N-terminal A (cid:2) PP fragments generated by alternative proteolytic processing of A (cid:2) PP may also be responsible for the divergent results obtained by…”
Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosisPreprint
Burrinha, T., Gomes, R. A., Terrasso, A. P., & Almeida, C. G. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/616540 · Cited by 4
Jadhav, D., Knapinska, A. M., Wang, H., & Fields, G. B. (2025) · Biomolecules · doi:10.3390/biom15081114 · Cited by 3
“Processing of CTF-η by ADAM10/17 and BACE1 releases A η - α (108 residues) and A η - β (92 residues), respectively (Figure 5) [32,42,69,70], which are synaptotoxic [32,66,71].”
InfluentialZhu, J., Xiao, X., Chen, X., Xiao, H., Tao, Z., Zhang, H., Park, K., Lam, L. Q., Thai, C., Trouson, B., et al. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251352213 · Cited by 3
Zhang, Y., Dong, M., Li, B.-L., & Sun, G. (2024) · Chaos Solitons & Fractals · doi:10.1016/j.chaos.2024.114867 · Cited by 3
Immuno-Nanotherapeutics Approach for the Treatment and Management of Alzheimer’s Disease
Bukhary, D. M. (2024) · International Journal of Pharmacology · doi:10.3923/ijp.2024.1365.1380 · Cited by 3
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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