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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BACE1 inhibitors were seen to increase cleavage of APP by other secretases, thereby enhancing production of pathogenic APP metabolites.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
Nikolaev, A., McLaughlin, T., O’Leary, D. D. M., & Tessier-Lavigne, M. (2009) · Nature · doi:10.1038/nature07767 · Cited by 992 · see citing works
RetractedR: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,706 · see citing works
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Cox, J., & Mann, M. (2008) · Nature Biotechnology · doi:10.1038/nbt.1511 · Cited by 14,855 · see citing works
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment
Cox, J., Neuhauser, N., Michalski, A., Scheltema, R. A., Olsen, J. V., & Mann, M. (2011) · Journal of Proteome Research · doi:10.1021/pr101065j · Cited by 5,349 · see citing works
Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961 · see citing works
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
Self-citationRappsilber, J., Mann, M., & Ishihama, Y. (2007) · Nature Protocols · doi:10.1038/nprot.2007.261 · Cited by 4,641 · see citing works
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291 · see citing works
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685 · see citing works
Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., et al. (2012) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.10.007 · Cited by 3,092 · see citing works
Self-citationAmyloid β-peptide is produced by cultured cells during normal metabolism
Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., Teplow, D. B., et al. (1992) · Nature · doi:10.1038/359322a0 · Cited by 1,921 · see citing works
Self-citationA mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012) · Nature · doi:10.1038/nature11283 · Cited by 1,738 · see citing works
Kaech, S., & Banker, G. A. (2006) · Nature Protocols · doi:10.1038/nprot.2006.356 · Cited by 1,705 · see citing works
Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J., & Sabatini, B. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4970-06.2007 · Cited by 1,592 · see citing works
In vivo two-photon calcium imaging of neuronal networks
Stosiek, C., Garaschuk, O., Holthoff, K., & Konnerth, A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1232232100 · Cited by 1,313 · see citing works
Self-citationProbing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., Hefferan, M. P., Van Gorp, S., Nazor, K. L., Boscolo, F. S., et al. (2012) · Nature · doi:10.1038/nature10821 · Cited by 1,253 · see citing works
Culturing hippocampal neurons.
Tanaka, H. (2002) · Folia Pharmacologica Japonica · doi:10.1254/fpj.119.163 · Cited by 1,141 · see citing works
Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer’s Disease
Busche, M. A., Eichhoff, G., Adelsberger, H., Abramowski, D., Wiederhold, K.-H., Haass, C., Staufenbiel, M., Konnerth, A., & Garaschuk, O. (2008) · Science · doi:10.1126/science.1162844 · Cited by 1,125 · see citing works
Self-citationHigher-energy C-trap dissociation for peptide modification analysis
Olsen, J., Macek, B., Lange, O., Makarov, A., Horning, S., & Mann, M. (2007) · Nature Methods · doi:10.1038/nmeth1060 · Cited by 1,007 · see citing works
Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology
Radde, R., Bolmont, T., Kaeser, S. A., Coomaraswamy, J., Lindau, D., Stoltze, L., Calhoun, M. E., Jäggi, F., Wolburg, H., Gengler, S., et al. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400784 · Cited by 986 · see citing works
Self-citationEngineering a memory with LTD and LTP
Nabavi, S., Fox, R., Proulx, C. D., Lin, J. Y., Tsien, R. Y., & Malinow, R. (2014) · Nature · doi:10.1038/nature13294 · Cited by 980 · see citing works
Shi, Y., Kirwan, P., & Livesey, F. J. (2012) · Nature Protocols · doi:10.1038/nprot.2012.116 · Cited by 972 · see citing works
Self-citationHaass, C., Koo, E., Mellon, A., Hung, A. Y., & Selkoe, D. (1992) · Nature · doi:10.1038/357500a0 · Cited by 901 · see citing works
Self-citationFunctional imaging of hippocampal place cells at cellular resolution during virtual navigation
Dombeck, D. A., Harvey, C. D., Tian, L., Looger, L. L., & Tank, D. W. (2010) · Nature Neuroscience · doi:10.1038/nn.2648 · Cited by 873 · see citing works
Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses
Shi, Y., Kirwan, P., Smith, J., Robinson, H. P. C., & Livesey, F. J. (2012) · Nature Neuroscience · doi:10.1038/nn.3041 · Cited by 813 · see citing works
Self-citationZhou, Z., Apte, S., Soininen, R., Cao, R., Baaklini, G. Y., Rauser, R. W., Wang, J., Cao, Y., & Tryggvason, K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.060037197 · Cited by 791 · see citing works
BACE1 is the major β-secretase for generation of Aβ peptides by neurons
Cai, H., Wang, Y.-S., McCarthy, D., Wen, H., Borchelt, D., Price, D. L., & Wong, P. (2001) · Nature Neuroscience · doi:10.1038/85064 · Cited by 791 · see citing works
Busche, M. A., Chen, X., Henning, H. A., Reichwald, J., Staufenbiel, M., Sakmann, B., & Konnerth, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206171109 · Cited by 715 · see citing works
Self-citationProcessing of the amyloid protein precursor to potentially amyloidogenic derivatives.
Golde, T., Estus, S., Younkin, L., Selkoe, D., & Younkin, S. (1992) · Science · doi:10.1126/science.1738847 · Cited by 710 · see citing works
Moechars, D., Dewachter, I., Lorent, K., Reversé, D., Baekelandt, V., Naidu, A., Tesseur, I., Spittaels, K., Haute, C. V. D., Checler, F., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6483 · Cited by 668 · see citing works
Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., Prinzen, C., Endres, K., Hiemke, C., Blessing, M., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20864 · Cited by 638 · see citing works
Targeting the β secretase BACE1 for Alzheimer's disease therapy
Yan, R., & Vassar, R. J. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70276-x · Cited by 628 · see citing works
Townsend, M., Shankar, G. M., Mehta, T., Walsh, D. M., & Selkoe, D. J. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2005.103754 · Cited by 619 · see citing works
Haass, C., Lemere, C. A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L., & Selkoe, D. J. (1995) · Nature Medicine · doi:10.1038/nm1295-1291 · Cited by 592 · see citing works
Self-citationTake five—BACE and the γ‐secretase quartet conduct Alzheimer's amyloid β‐peptide generation
Haass, C. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600061 · Cited by 547 · see citing works
Self-citationbeta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms.
Haass, C., Hung, A. Y., Schlossmacher, M. G., Teplow, D. B., & Selkoe, D. J. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53650-4 · Cited by 465 · see citing works
Self-citationPotentially Amyloidogenic, Carboxyl-Terminal Derivatives of the Amyloid Protein Precursor
Estus, S., Golde, T. E., Kunishita, T., Blades, D. A., Lowery, D. E., Eisen, M., Usiak, M., QU, X., Tabira, T., Greenberg, B., et al. (1992) · Science · doi:10.1126/science.1738846 · Cited by 431 · see citing works
Podlisny, M. B., Ostaszewski, B. L., Squazzo, S. L., Koo, E. H., Rydel, R. E., Teplow, D. B., & Selkoe, D. J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.16.9564 · Cited by 364 · see citing works
Proteomic Characterization of Postmortem Amyloid Plaques Isolated by Laser Capture Microdissection
Liao, L., Cheng, D., Wang, J., Duong, D. M., Losik, T. G., Gearing, M., Rees, H. D., Lah, J. J., Levey, A. I., & Peng, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403672200 · Cited by 323 · see citing works
Scheltema, R. A., Hauschild, J.-P., Lange, O., Hornburg, D., Denisov, E. V., Damoc, E., Kuehn, A., Makarov, A., & Mann, M. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.043489 · Cited by 321 · see citing works
Self-citationSecretome protein enrichment identifies physiological BACE1 protease substrates in neurons
Kuhn, P., Koroniak–Szejn, K., Hogl, S., Colombo, A. V., Zeitschel, U., Willem, M., Volbracht, C., Schepers, U., Imhof, A., Hoffmeister, A., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.173 · Cited by 318 · see citing works
Self-citationMüller, U. (1994) · Cell · doi:10.1016/0092-8674(94)90066-3 · Cited by 308 · see citing works
Self-citationMcConlogue, L., Buttini, M., Anderson, J. P., Brigham, E. F., Chen, K. S., Freedman, S. B., Games, D., Johnson-Wood, K., Lee, M., Zeller, M., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611687200 · Cited by 300 · see citing works
NMDA Receptor-Dependent Multidendrite Ca 2+ Spikes Required for Hippocampal Burst Firing In Vivo
Grienberger, C., Chen, X., & Konnerth, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.014 · Cited by 185 · see citing works
Self-citationHigh-ResolutionIn VivoImaging of Hippocampal Dendrites and Spines
Mizrahi, A., Crowley, J. C., Shtoyerman, E., & Katz, L. C. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.5218-03.2004 · Cited by 174 · see citing works
The Neural Cell Adhesion Molecules L1 and CHL1 Are Cleaved by BACE1 Protease in Vivo*
Zhou, L., Barão, S., Laga, M., Bockstael, K., Borgers, M., Gijsen, H., Annaert, W., Moechars, D., Mercken, M., Gevaer, K., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.377465 · Cited by 172 · see citing works
Simons, M., Strooper, B. D., Multhaup, G., Tienari, P. J., Dotti, C. G., & Beyreuther, K. T. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-03-00899.1996 · Cited by 161 · see citing works
Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions
Filser, S., Ovsepian, S. V., Masana, M., Blázquez‐Llorca, L., Elvang, A. B., Volbracht, C., Müller, M. B., Jung, C. K. E., & Herms, J. W. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.10.013 · Cited by 131 · see citing works
Self-citationFleck, D., van Bebber, F., Colombo, A. V., Galante, C., Schwenk, B. M., Rabe, L., Hampel, H., Novak, B., Kremmer, E., Tahirović, S., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3372-12.2013 · Cited by 129 · see citing works
Self-citationDimerization of β-Site β-Amyloid Precursor Protein-cleaving Enzyme
Westmeyer, G. G., Willem, M., Lichtenthaler, S. F., Lurman, G. J., Multhaup, G., Assfalg‐Machleidt, I., Reiß, K., Säftig, P., & Haass, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410378200 · Cited by 108 · see citing works
Self-citationSekine‐Aizawa, Y., Hama, E., Watanabe, K., Tsubuki, S., Kanai‐Azuma, M., Kanai, Y., Arai, H., Aizawa, H., Iwata, N., & Saido, T. C. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01462.x · Cited by 108 · see citing works
Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo
Jefferson, T., Čaušević, M., Keller, U. A. D., Schilling, O., Isbert, S., Geyer, R., Maier, W., Tschickardt, S., Jumpertz, T., Weggen, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.252718 · Cited by 105 · see citing works
Welzel, A. T., Maggio, J. E., Shankar, G. M., Walker, D., Ostaszewski, B. L., Li, S., Klyubin, I. V., Rowan, M. J., Seubert, P. A., Walsh, D. M., et al. (2014) · Biochemistry · doi:10.1021/bi5003053 · Cited by 97 · see citing works
Jacobsen, H., Ozmen, L., Caruso, A., Narquizian, R., Hilpert, H., Jacobsen, B., Terwel, D., An, T.-H., & Bohrmann, B. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1405-14.2014 · Cited by 93 · see citing works
Folgueras, A. R., Valdés‐Sánchez, T., Llano, E., Menéndez, L., Baamonde, A., Denlinger, B. L., Belmonte, C., Juárez, L. L., Lastra, A., García‐Suárez, O., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908507106 · Cited by 91 · see citing works
Amyloid precursor protein mutation causes Alzheimer's disease in a Swedish family
Lannfelt, L., Bogdanović, N., Appelgren, H., Axelman, K., Lilius, L., Hansson, G. K., Schenk, D., Hardy, J., & Winblad, B. G. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90463-4 · Cited by 89 · see citing works
Self-citationFunction, regulation and therapeutic properties of β-secretase (BACE1)
Willem, M., Lammich, S., & Haass, C. (2009) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2009.01.003 · Cited by 86 · see citing works
Self-citationHigashi, S., & Miyazaki, K. (2003) · Biochemistry · doi:10.1021/bi020643m · Cited by 53 · see citing works
Portelius, E., Olsson, M., Brinkmalm, G., Rüetschi, U., Mattsson, N., Andréasson, U., Gobom, J., Brinkmalm, A., Hölttä, M., Blennow, K., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120994 · Cited by 50 · see citing works
Houeland, G., Romani, A., Marchetti, C., Amato, G., Capsoni, S., Cattaneo, A., & Marie, H. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0457-10.2010 · Cited by 46 · see citing works
Self-citationCNS Amyloid- , Soluble APP- and - Kinetics during BACE Inhibition
Zakaria, J. A. D., Michener, M. S., Wu, G., Patterson, B. W., Chott, R. C., Ovod, V., Pyatkivskyy, Y., Wildsmith, K. R., Kasten, T. L., Mathers, P. D., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0540-14.2014 · Cited by 39 · see citing works
Lannfelt, L., Basun, H., Vigo-Pelfrey, C., Wahlund, L.-O., Winblad, B., Lieberburg, I., & Schenk, D. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)12059-d · Cited by 39 · see citing works
Self-citationCurrent and Emerging Therapies for Alzheimer’s Disease
Nygaard, H. B. (2013) · Clinical Therapeutics · doi:10.1016/j.clinthera.2013.09.009 · Cited by 32 · see citing works
Vella, L. J., & Cappai, R. (2012) · The FASEB Journal · doi:10.1096/fj.11-200295 · Cited by 27 · see citing works
Semagacestat's fall: where next for AD therapies?
(2013) · Nature Medicine · doi:10.1038/nm.3365 · Cited by 24 · see citing works
Self-citationNolan, R., & Teller, J. K. (2006) · Journal of Biochemical and Biophysical Methods · doi:10.1016/j.jbbm.2006.04.002 · Cited by 19 · see citing works
Cleavage of Amyloid-β Precursor Protein (APP) by Membrane-Type Matrix Metalloproteinases
Ahmad, M., Takino, T., Miyamori, H., Yoshizaki, T., Furukawa, M., & Sato, H. (2006) · The Journal of Biochemistry · doi:10.1093/jb/mvj054
Flagged first, then by citations
Research works printed but not linked: 2
- [34]Radde R A beta 42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology EMBO Rep 2006 7 940 946 16906128 PMC1559665
- [50]Jacobsen H Combined treatment with a BACE inhibitor and anti-Ab antibody gantenerumab enhances amyloid reduction in APPLondon mice J Neurosci 2014 in press PMC4145168 25164658
Cited by
Sorted by citations
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Scheltens, P., Blennow, K., Breteler, M. M. B., de Strooper, B., Frisoni, G. B., Salloway, S., & Van der Flier, W. M. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01124-1 · Cited by 3,125 · see citing works
Oxidative stress and the amyloid beta peptide in Alzheimer’s disease
Cheignon, C., Tomas, M., Bonnefont-Rousselot, D., Faller, P., Hureau, C., & Collin, F. (2018) · Redox Biology · doi:10.1016/j.redox.2017.10.014 · Cited by 2,185 · see citing works
“A third way of APP cleavage has been recently discovered [21].”
BackgroundThe Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952 · see citing works
Self-citationMolecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
“η-secretase-mediated APP cleavage releases a soluble APPη ectodomain and retains a membrane bound η-CTF product [36].”
BackgroundNetwork abnormalities and interneuron dysfunction in Alzheimer disease
Palop, J. J., & Mucke, L. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.141 · Cited by 1,022 · see citing works
APP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793 · see citing works
The β-Secretase BACE1 in Alzheimer’s Disease
Hampel, H., Vassar, R., De Strooper, B., Hardy, J., Willem, M., Singh, N., Zhou, J., Yan, R., Vanmechelen, E., De Vos, A., et al. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.02.001 · Cited by 694 · see citing works
Self-citationNot just amyloid: physiological functions of the amyloid precursor protein family
Müller, U. C., Deller, T., & Korte, M. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.29 · Cited by 634 · see citing works
Self-citationThe road to restoring neural circuits for the treatment of Alzheimer's disease
Canter, R. G., Penney, J., & Tsai, L.-H. (2016) · Nature · doi:10.1038/nature20412 · Cited by 565 · see citing works
Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 454 · see citing works
Kennedy, M., Stamford, A., Chen, X., Cox, K., Cumming, J., Dockendorf, M., Egan, M. F., Ereshefsky, L., Hodgson, R., Hyde, L., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad9704 · Cited by 391 · see citing works
The role of matrix metalloproteinases in aging: Tissue remodeling and beyond
Freitas‐Rodríguez, S., Folgueras, A. R., & López-Otı́n, C. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.05.007 · Cited by 367 · see citing works
Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Schlepckow, K., Monroe, K. M., Kleinberger, G., Cantuti‐Castelvetri, L., Parhizkar, S., Xia, D., Willem, M., Werner, G., Pettkus, N., Brunner, B., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201911227 · Cited by 324 · see citing works
“…NaCl, pH 10, and protease inhibitor mix [Sigma, P8340]) and RIPA lysates (20 mM Tris–HCl [pH 7.5], 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% NP-40, 1% sodium deoxycholate, 2.5 mM sodium pyrophosphate, and protease inhibitor mix [Sigma, P8340]) were prepared from brain hemispheres (Willem et al, 2015).”
MethodInfluentialSelf-citationImbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease
Styr, B., & Slutsky, I. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0080-x · Cited by 314 · see citing works
Sadleir, K. R., Kandalepas, P. C., Buggia-Prévot, V., Nicholson, D. A., Thinakaran, G., & Vassar, R. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1558-9 · Cited by 294 · see citing works
“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 298 · see citing works
“MT5-MMP was recently furthermore identified as the APP g - secretase, and its inactivation reduced inflammation and amyloid pathology in an Alzheimer’s disease mouse model (Willem et al , 2015; Baranger et al , 2016).”
Rice, H. C., de Malmazet, D., Schreurs, A., Frere, S., Van Molle, I., Volkov, A. N., Creemers, E., Vertkin, I., Nys, J., Ranaivoson, F. M., et al. (2019) · Science · doi:10.1126/science.aao4827 · Cited by 281 · see citing works
“sAPPb-Fc and sAPPh-Fc, a product of the recently described h-secretase processing pathway (6), which both contain the ExD, also bound to GABABR1a-expressing cells (Fig.”
BackgroundSexual dimorphism in predisposition to Alzheimer's disease
Fisher, D. W., Bennett, D. A., & Dong, H. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.04.004 · Cited by 270 · see citing works
Oxidative stress and mitochondrial impairment: Key drivers in neurodegenerative disorders
Wen, P., Sun, Z., Gou, F., Wang, J., Fan, Q., Zhao, D., & Yang, L. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102667 · Cited by 253 · see citing works
Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Pagnotta, S., Biferi, M.-G., Barkats, M., Lacor, P., Klein, W., Bauer, C., & Checler, F. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1577-6 · Cited by 219 · see citing works
“1 3 this fragment, it could possibly correspond to the recently described ƞ-secretase-derived APP-CTF [2, 59].”
BackgroundGunhanlar, N., Shpak, G., van der Kroeg, M., Gouty‐Colomer, L., Munshi, S. T., Lendemeijer, B., Ghazvini, M., Dupont, C., Hoogendijk, W. J. G., Gribnau, J. H., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.56 · Cited by 219 · see citing works
What Happens with the Circuit in Alzheimer's Disease in Mice and Humans?
Zott, B., Busche, M. A., Sperling, R. A., & Konnerth, A. (2018) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-080317-061725 · Cited by 215 · see citing works
“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).”
BackgroundSelf-citationThe alpha secretase ADAM10: A metalloprotease with multiple functions in the brain
Säftig, P., & Lichtenthaler, S. F. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.10.003 · Cited by 209 · see citing works
MMPs in learning and memory and neuropsychiatric disorders
Beroun, A., Mitra, S., Michaluk, P., Pijet, B., Stefaniuk, M., & Kaczmarek, L. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03180-8 · Cited by 207 · see citing works
“Additionally, MT5MMP is capable of cleaving β-amyloid precursor protein (APP) creating carboxy-terminal fragments of APP, which are able to impair hippocampal LTP as well as reduce neuronal activity in vivo [142].”
BackgroundTREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance
Xiang, X., Werner, G., Bohrmann, B., Liesz, A., Mazaheri, F., Capell, A., Feederle, R., Knuesel, I., Kleinberger, G., & Haass, C. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606370 · Cited by 183 · see citing works
“Similarly, recent findings may also indicate that inhibition of b-secretase may be problematic due to the accumulation of alternative neurotoxic APP-derived fragments (Willem et al, 2015).”
Self-citationCalcium/calmodulin-dependent kinase II and Alzheimer’s disease
Ghosh, A., & Giese, K. P. (2015) · Molecular Brain · doi:10.1186/s13041-015-0166-2 · Cited by 205 · see citing works
“New evidence suggests alternative proteolytic pathways of APP by η-secretases can lead to production of a toxic amyloid-η (Aη) species that can also contribute to AD pathology [11].”
BackgroundDiagnostic and therapeutic potential of exosomes in Alzheimer’s disease
Martins, T. S., Trindade, D., Vaz, M., Campelo, I., Almeida, M., Trigo, G., Silva, O. A. B. D. C. E., & Henriques, A. G. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15112 · Cited by 174 · see citing works
“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).”
BackgroundA Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis *
Andrew, R., Kellett, K., Thinakaran, G., & Hooper, N. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.746032 · Cited by 156 · see citing works
“Aη-α -Inhibited LTP in hippocampal brain slices from mice and supressed activity in hippocampal neurons (23).”
InfluentialModifications and Trafficking of APP in the Pathogenesis of Alzheimer’s Disease
Wang, X., Zhou, X., Li, G., Zhang, Y., Wu, Y., & Song, W. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00294 · Cited by 173 · see citing works
“C191 is enriched in an AD mouse model and human AD brains and it could be further processed by α- and β-secretase generating Aη-α and Aη-β, respectively (Figure 1; Willem et al., 2015).”
BackgroundInfluentialCellular and Molecular Mechanisms of Prion Disease
Sigurdson, C. J., Bartz, J. C., & Glatzel, M. (2018) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012418-013109 · Cited by 171 · see citing works
“This is reminiscent of functions attributed to proteolytic cleavage fragments from the amyloid precursor protein (APP) (63, 64).”
BackgroundBACE1 Physiological Functions May Limit Its Use as Therapeutic Target for Alzheimer's Disease.
Barão, S., Moechars, D., Lichtenthaler, S., & de Strooper, B. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.01.003 · Cited by 161 · see citing works
Laulagnier, K., Javalet, C., Hemming, F. J., Chivet, M., Lachenal, G. M., Blot, B., Chatellard, C., & Sadoul, R. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2664-0 · Cited by 169 · see citing works
Hong, W., Wang, Z., Liu, W., O’Malley, T. T., Jin, M., Willem, M., Haass, C., Frosch, M. P., & Walsh, D. M. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1846-7 · Cited by 166 · see citing works
“However, recent evidence suggests that a variety of APP fragments which contain all or part of the Aβ sequence may have disease-relevant activity [56, 57].”
InfluentialSelf-citationHarris, S. S., Wolf, F., De Strooper, B., & Busche, M. A. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.005 · Cited by 161 · see citing works
“However, in striking contrast to the effects of Ab on neuronal excitability (described earlier), Ah-a strongly suppresses ongoing neuronal activity in vivo and thus could antagonize Ab neuronal effects (Willem et al., 2015).”
BackgroundMethodResultInfluentialSelf-citationThe Role of ADAM10 in Alzheimer’s Disease
Yuan, X., Sun, S., Tan, C., Yu, J., & Tan, L. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170061 · Cited by 160 · see citing works
Toward more predictive genetic mouse models of Alzheimer’s disease
Onos, K. D., Sukoff Rizzo, S. J., Howell, G. R., & Sasner, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2015.12.003 · Cited by 156 · see citing works
Wang, Z., Jackson, R. J., Hong, W., Taylor, W. M., Corbett, G. T., Moreno, A. J., Liu, W., Li, S., Frosch, M. P., Slutsky, I., et al. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2009-17.2017 · Cited by 154 · see citing works
Amyloid β-protein and beyond: the path forward in Alzheimer’s disease
Walsh, D. M., & Selkoe, D. J. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.02.003 · Cited by 160 · see citing works
Kwak, S. S., Washicosky, K. J., Brand, E., von Maydell, D., Aronson, J., Kim, S., Capen, D. E., Cetinbas, M., Sadreyev, R., Ning, S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15120-3 · Cited by 151 · see citing works
Millan, M. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.004 · Cited by 146 · see citing works
Cell Biology of Prions and Prionoids: A Status Report
Aguzzi, A., & Lakkaraju, A. K. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.08.007 · Cited by 142 · see citing works
“Many different peptides [126] are generated in vivo, of which Ab1–42 has the highest propensity to aggregate [23].”
BackgroundThe case for low-level BACE1 inhibition for the prevention of Alzheimer disease
McDade, E., Voytyuk, I., Aisen, P., Bateman, R., Carrillo, M., de Strooper, B., Haass, C., Reiman, E., Sperling, R., Tariot, P., et al. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00545-1 · Cited by 129 · see citing works
Self-citationTan, J. Z. A., & Gleeson, P. A. (2019) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.11.013 · Cited by 126 · see citing works
BACE inhibition-dependent repair of Alzheimer’s pathophysiology
Keskin, A. D., Kekuš, M., Adelsberger, H., Neumann, U., Shimshek, D. R., Song, B., Zott, B., Peng, T., Förstl, H., Staufenbiel, M., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1708106114 · Cited by 125 · see citing works
“These peptides can effectively promote neuronal silencing and impair hippocampal long-term potentiation in mice (31).”
BackgroundSelf-citationUpstream regulators and downstream effectors of NF-κB in Alzheimer’s disease
Shi, Z.-M., Han, Y.-W., Han, X.-H., Zhang, K., Chang, Y.-N., Hu, Z.-M., Qi, H.-X., Ting, C., Zhen, Z., & Hong, W. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.05.022 · Cited by 125 · see citing works
Alić, I., Goh, P. A., Murray, A., Portelius, E., Gkanatsiou, E., Gough, G., Mok, K. Y., Koschut, D., Brunmeir, R., Yeap, Y. J., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-0806-5 · Cited by 123 · see citing works
Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics
Sala Frigerio, C., & De Strooper, B. (2016) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070815-014015 · Cited by 116 · see citing works
“…might favor the production of toxic peptides through other pathways, as shown in the recent paper of the Haass laboratory identifying a novel η-secretase-cleaved fragment of APP that affects synaptic transmission and whose production is increased following BACE1 inhibition (Willem et al. 2015).”
APP/Aβ structural diversity and Alzheimer's disease pathogenesis
Roher, A. E., Kokjohn, T. A., Clarke, S. G., Sierks, M. R., Maarouf, C. L., Serrano, G. E., Sabbagh, M., & Beach, T. G. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.08.007 · Cited by 121 · see citing works
Dynamics of Human Mitochondrial Complex I Assembly: Implications for Neurodegenerative Diseases
Giachin, G., Bouverot, R., Acajjaoui, S., Pantalone, S., & Soler‐López, M. (2016) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2016.00043 · Cited by 117 · see citing works
Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα
Mockett, B. G., Richter, M., Abraham, W. C., & Müller, U. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00030 · Cited by 115 · see citing works
“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).”
BackgroundSelf-citationMKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models
Du, Y., Du, Y., Zhang, Y., Huang, Z., Fu, M., Li, J., Pang, Y., Lei, P., Wang, Y. T., Song, W., et al. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0091-4 · Cited by 117 · see citing works
Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?
Dunys, J., Valverde, A., & Checler, F. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.r118.003999 · Cited by 71 · see citing works
Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer’s brain
Brinkmalm, G., Hong, W., Wang, Z., Liu, W., O’Malley, T. T., Sun, X., Frosch, M. P., Selkoe, D. J., Portelius, E., Zetterberg, H., et al. (2019) · Brain · doi:10.1093/brain/awz066 · Cited by 114 · see citing works
“However, the molecular identity of ~7 kDa Aβ is controversial (Watt et al., 2013; Willem et al., 2015) and definitive identification has been hampered due to the low abundance of ~7 kDa Aβ.”
BackgroundRivera, S., García‐González, L., Khrestchatisky, M., & Baranger, K. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03178-2 · Cited by 112 · see citing works
SIRT3 and mitochondrial metabolism in neurodegenerative diseases
Salvatori, I., Valle, C., Ferri, A., & Carrı̀, M. T. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.04.012 · Cited by 112 · see citing works
APP Receptor? To Be or Not To Be
Deyts, C., Thinakaran, G., & Parent, A. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.01.005 · Cited by 109 · see citing works
“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 · see citing works
“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 106 · see citing works
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 104 · see citing works
“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 · see citing works
Yuksel, M., & Tacal, Ö. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172415 · Cited by 94 · see citing works
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 · see citing works
Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease
Andersen, O. M., Rudolph, I., & Willnow, T. E. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1615-4 · Cited by 89 · see citing works
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 84 · see citing works
Synaptic 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 88 · see citing works
Chen, J., Wang, J., Yin, B., Pang, L., Wang, W., & Zhu, W. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00348 · Cited by 84 · see citing works
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 · see citing works
“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 · see citing works
“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 81 · see citing works
“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 82 · see citing works
“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.”
BackgroundInfluentialGarcía-González, L., Pilat, D., Baranger, K., & Rivera, S. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00244 · Cited by 65 · see citing works
“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).”
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 · see citing works
“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 · see citing works
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 76 · see citing works
“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 · see citing works
“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 78 · see citing works
“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 78 · see citing works
“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 74 · see citing works
“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 75 · see citing works
“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 74 · see citing works
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 · see citing works
“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 · see citing works
“, 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 69 · see citing works
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 69 · see citing works
“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 · see citing works
“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 · see citing works
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 68 · see citing works
“…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 · see citing works
“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 53 · see citing works
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) · The Journal of Cell Biology · doi:10.1083/jcb.201806205 · Cited by 68 · see citing works
“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 48 · see citing works
“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 · see citing works
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 64 · see citing works
“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 63 · see citing works
Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease
Eysert, F., Kinoshita, P., Mary, A., Vaillant-Beuchot, L., Checler, F., & Chami, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249521 · Cited by 53 · see citing works
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 61 · see citing works
“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 59 · see citing works
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 · see citing works
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 57 · see citing works
“In addition, a recent paper described the formation of novel, toxic A fragments derived from larger APP CTFs (46).”
Background
- 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
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
