amyloid precursor protein secretases


Summary: Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.

Top Publications

  1. Asai M, Kawakubo T, Mori R, Iwata N. Elucidating Pathogenic Mechanisms of Early-onset Alzheimer's Disease in Down Syndrome Patients. Yakugaku Zasshi. 2017;137:801-805 pubmed publisher
    ..Our results suggest that DYRK1A inhibitors could be effective against AD not only in adults with DS but also in sporadic AD patients. ..
  2. Furukawa K, Sopher B, Rydel R, Begley J, Pham D, Martin G, et al. Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem. 1996;67:1882-96 pubmed
  3. Hartmann T, Bieger S, Brühl B, Tienari P, Ida N, Allsop D, et al. Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides. Nat Med. 1997;3:1016-20 pubmed
    ..We suggest that the earliest event taking place in AD might be the generation of A beta(1-42) in the ER. ..
  4. Yuksel M, Biberoglu K, Onder S, Akbulut K, Tacal O. Effects of phenothiazine-structured compounds on APP processing in Alzheimer's disease cellular model. Biochimie. 2017;138:82-89 pubmed publisher
    ..Taken together, our results represent the first report demonstrating that TBO and TH can affect amyloid metabolism in vitro. ..
  5. Mamada N, Tanokashira D, Ishii K, Tamaoka A, Araki W. Mitochondria are devoid of amyloid ?-protein (A?)-producing secretases: Evidence for unlikely occurrence within mitochondria of A? generation from amyloid precursor protein. Biochem Biophys Res Commun. 2017;486:321-328 pubmed publisher
    ..In view of the particularly low expression levels of BACE1, ?-secretase complex proteins, and ?-CTF in mitochondria, we propose that it is unlikely that A? generation from APP occurs locally within this organelle. ..
  6. Sokołowska I, Piłka E, Sandvig K, Wegrzyn G, Słomińska Wojewódzka M. Hydrophobicity of protein determinants influences the recognition of substrates by EDEM1 and EDEM2 in human cells. BMC Cell Biol. 2015;16:1 pubmed publisher
    ..Moreover, EDEM proteins can bind hydrophobic transmembrane regions of misfolded ERAD substrates. These data contribute to the general understanding of the regulation of ERAD in mammalian cells. ..
  7. Yan G, Hao L, Niu Y, Huang W, Wang W, Xu F, et al. 2-Substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and docking studies. Eur J Med Chem. 2017;137:462-475 pubmed publisher
    ..The studies revealed that the most potent analog 41 (IC50 = 4.6 ?M) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization. ..
  8. Coulson E, Bartlett P. An exercise path to preventing Alzheimer's disease: An Editorial Highlight on 'Exercise and BDNF reduce Ab production by enhancing ?-secretase processing of APP'. J Neurochem. 2017;142:191-193 pubmed publisher
    ..Read the highlighted article 'Exercise and BDNF reduce A? production by enhancing ?-secretase processing of APP' on page 286. ..
  9. Saint Pol J, Billard M, Dornier E, Eschenbrenner E, Danglot L, Boucheix C, et al. New insights into the tetraspanin Tspan5 using novel monoclonal antibodies. J Biol Chem. 2017;292:9551-9566 pubmed publisher

More Information


  1. Gunawardena S, Yang G, Goldstein L. Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo. Hum Mol Genet. 2013;22:3828-43 pubmed publisher
    ..Thus, perturbations of APP/PS transport could contribute to early neuropathology observed in AD, and highlight a potential novel therapeutic pathway for early intervention, prior to neuronal loss and clinical manifestation of disease. ..
  2. Cummings J. What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease?. Biol Psychiatry. 2010;68:876-8 pubmed publisher
  3. Moussa C. Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer's disease. Expert Opin Investig Drugs. 2017;26:1131-1136 pubmed publisher
    ..We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of A? alone and pay more attention to simultaneous clearance of tau and A?. ..
  4. Stubblefield K, Chean J, Nguyen T, Chen C, Shively J. The adaptor SASH1 acts through NOTCH1 and its inhibitor DLK1 in a 3D model of lumenogenesis involving CEACAM1. Exp Cell Res. 2017;359:384-393 pubmed publisher
  5. Shi L, Ma Y, Zheng C, Zhang Q. The effect of blocking Notch signaling by ?-secretase inhibitor on allergic rhinitis. Int J Pediatr Otorhinolaryngol. 2017;98:32-38 pubmed publisher
    ..Our findings provide evidence that blocking Notch signaling by GSI offers high value in treating AR. ..
  6. Bolduc D, Wolfe M. Structure of nicastrin unveils secrets of ?-secretase. Proc Natl Acad Sci U S A. 2014;111:14643-4 pubmed publisher
  7. Choi G, Lee S, Lee H, Ko S, Chae C, Han H. Membrane-Associated Effects of Glucocorticoid on BACE1 Upregulation and A? Generation: Involvement of Lipid Raft-Mediated CREB Activation. J Neurosci. 2017;37:8459-8476 pubmed publisher
    ..In this study, we revealed the importance of nongenomic pathway induced by glucocorticoid where membrane glucocorticoid receptor plays an important role in A? formation. ..
  8. Maoz R, Garfinkel B, Soreq H. Alzheimer's Disease and ncRNAs. Adv Exp Med Biol. 2017;978:337-361 pubmed publisher
    ..Finally, we explore the potential promise of these findings for future therapeutic applications. ..
  9. Di Pietro O, Juárez Jiménez J, Muñoz Torrero D, Laughton C, Luque F. Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors. PLoS ONE. 2017;12:e0177683 pubmed publisher
    ..Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors. ..
  10. Warchol M, Stone J, Barton M, Ku J, Veile R, Daudet N, et al. ADAM10 and ?-secretase regulate sensory regeneration in the avian vestibular organs. Dev Biol. 2017;428:39-51 pubmed publisher
    ..Together, our data suggest multiple roles for ?-secretase and ADAM10 in vestibular hair cell regeneration. ..
  11. Kang J, Shin S, Perrimon N, Shen J. An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain. Genetics. 2017;206:1479-1493 pubmed publisher
  12. Yan Y, Xu T, Harikumar K, Miller L, Melcher K, Xu H. Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the ?-secretase cleavage sites. J Biol Chem. 2017;292:15826-15837 pubmed publisher
    ..These four amino acids are also a hot spot of familial Alzheimer's disease-linked mutations that both decrease C99 homodimerization and ?-secretase cleavage and alter the initial cleavage site to increase the A?42/40 ratio. ..
  13. Ye X, Feng T, Tammineni P, Chang Q, Jeong Y, Margolis D, et al. Regulation of Synaptic Amyloid-? Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease. J Neurosci. 2017;37:2639-2655 pubmed publisher
    ..Our study uncovers a new pathway that controls synaptic APP processing by enhancing axonal BACE1 trafficking, thereby advancing our fundamental knowledge critical for ameliorating A?-linked synaptic pathology. ..
  14. Huang M, Jiang X, Liang Y, Liu Q, Chen S, Guo Y. Berberine improves cognitive impairment by promoting autophagic clearance and inhibiting production of ?-amyloid in APP/tau/PS1 mouse model of Alzheimer's disease. Exp Gerontol. 2017;91:25-33 pubmed publisher
    ..In summary, berberine shows neuroprotective effects on 3×Tg-AD mice and may be a promising multitarget drug in the preventionand protection against AD. ..
  15. Shi Z, Chen T, Yao Q, Zheng L, Zhang Z, Wang J, et al. The circular RNA ciRS-7 promotes APP and BACE1 degradation in an NF-?B-dependent manner. FEBS J. 2017;284:1096-1109 pubmed publisher
    ..Taken together, our data provide a molecular mechanism implicating reduced ciRS-7 expression in AD, suggesting that ciRS-7 may represent a useful target in the development of therapeutic strategies for AD. ..
  16. Zhao X, Gong D, Jiang Y, Guo D, Zhu Y, Deng Y. Multipotent AChE and BACE-1 inhibitors for the treatment of Alzheimer's disease: Design, synthesis and bio-analysis of 7-amino-1,4-dihydro-2H-isoquilin-3-one derivates. Eur J Med Chem. 2017;138:738-747 pubmed publisher
    ..68 ± 8.01% at 20 ?M), and good metal chelating property, which can be chosen as lead compound for further optimization of novel small ligand for the treatment of Alzheimer's disease. ..
  17. Liao F, Wang R, Park E. Repression of Alzheimer's beta-secretase. Aging (Albany NY). 2013;5:789-90 pubmed
  18. Bernstein H, Lendeckel U, Steiner J, Bogerts B. Oestrogen downregulates BACE protein in human cell culture: what does this teach us about Alzheimer's disease?. Neurodegener Dis. 2011;8:153-4 pubmed publisher
  19. Lo A, Haass C, Wagner S, Teplow D, Sisodia S. Metabolism of the "Swedish" amyloid precursor protein variant in Madin-Darby canine kidney cells. J Biol Chem. 1994;269:30966-73 pubmed
    ..Finally, we demonstrate that A beta is secreted into the basolateral compartment of SWE cells and that the majority of these A beta-related species contains an amino-terminal aspartate residue (+1). ..
  20. Zhang S, Wang Z, Cai F, Zhang M, Wu Y, Zhang J, et al. BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. J Neurosci. 2017;37:6915-6925 pubmed publisher
  21. Sheridan C. Pivotal trials for ?-secretase inhibitors in Alzheimer's. Nat Biotechnol. 2015;33:115-6 pubmed publisher
  22. Haghighijoo Z, Firuzi O, Hemmateenejad B, Emami S, Edraki N, Miri R. Synthesis and biological evaluation of quinazolinone-based hydrazones with potential use in Alzheimer's disease. Bioorg Chem. 2017;74:126-133 pubmed publisher
    ..These results demonstrate that quinazolinone-hydrazone derivatives represent a valuable scaffold for the discovery of novel non-peptidic BACE1 inhibitors. ..
  23. Nomura Y, Nomura T, Suzuki S, Takeda M, Mizuno O, Ohguchi Y, et al. A novel NCSTN mutation alone may be insufficient for the development of familial hidradenitis suppurativa. J Dermatol Sci. 2014;74:180-2 pubmed publisher
  24. Du X, Huo X, Yang Y, Hu Z, Botchway B, Jiang Y, et al. miR-124 downregulates BACE 1 and alters autophagy in APP/PS1 transgenic mice. Toxicol Lett. 2017;280:195-205 pubmed publisher
    ..In view of this, we hypothesis that miR-124 conducts its neuroprotective effect through BACE 1 by regulation of autophagic pathways. ..
  25. Xie H, Zhao Y, Zhou Y, Liu L, Liu Y, Wang D, et al. MiR-9 Regulates the Expression of BACE1 in Dementia Induced by Chronic Brain Hypoperfusion in Rats. Cell Physiol Biochem. 2017;42:1213-1226 pubmed publisher
    ..We conclude that miR-9 plays an important role in regulating the process of dementia induced by 2VO in rats by increasing BACE1 expression via downregulation of CREB. ..
  26. Seegar T, Killingsworth L, Saha N, Meyer P, Patra D, Zimmerman B, et al. Structural Basis for Regulated Proteolysis by the ?-Secretase ADAM10. Cell. 2017;171:1638-1648.e7 pubmed publisher
    ..Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation. ..
  27. Perneczky R, Alexopoulos P, Kurz A. Soluble amyloid precursor proteins and secretases as Alzheimer's disease biomarkers. Trends Mol Med. 2014;20:8-15 pubmed
    ..Here we review evidence on the APP processing enzymes and their cleavage products and discuss possible applications and limitations in their use as AD biomarkers. ..
  28. Pink A, Simpson M, Desai N, Dafou D, Hills A, Mortimer P, et al. Mutations in the ?-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). J Invest Dermatol. 2012;132:2459-2461 pubmed publisher
  29. Yang Z, Li P, Chen R, Wang J, Wang S, Shen Y, et al. ADAM10-Initiated Release of Notch Intracellular Domain Regulates Microtubule Stability and Radial Migration of Cortical Neurons. Cereb Cortex. 2017;27:919-932 pubmed publisher
  30. Citron M, Teplow D, Selkoe D. Generation of amyloid beta protein from its precursor is sequence specific. Neuron. 1995;14:661-70 pubmed
    ..Our results have important implications for current intensive approaches to develop assays for and identify enzymes with beta-secretase activity. ..
  31. Welzel A, Maggio J, Shankar G, Walker D, Ostaszewski B, Li S, et al. Secreted amyloid ?-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity. Biochemistry. 2014;53:3908-21 pubmed
    ..We conclude that certain synaptotoxic A?-containing species can arise from APP processing events N-terminal to the classical ?-secretase cleavage site. ..
  32. Newman M, Halter L, Lim A, Lardelli M. Mitochondrion to endoplasmic reticulum apposition length in zebrafish embryo spinal progenitors is unchanged in response to perturbations associated with Alzheimer's disease. PLoS ONE. 2017;12:e0179859 pubmed publisher
    ..Future examination of more differentiated, more secretory cell types may reveal measurable responses of M-ER apposition to environmental and genetic manipulation. ..
  33. Chami M, Halmer R, Schnoeder L, Anne Becker K, Meier C, Fassbender K, et al. Acid sphingomyelinase deficiency enhances myelin repair after acute and chronic demyelination. PLoS ONE. 2017;12:e0178622 pubmed publisher
    ..These findings suggest that acid sphingomyelinase plays a significant role in myelin repair, and its inhibition by amitriptyline may constitute a novel therapeutic approach for multiple sclerosis patients. ..
  34. Querfurth H, LaFerla F. Alzheimer's disease. N Engl J Med. 2010;362:329-44 pubmed publisher
  35. López Juárez A, Titus H, Silbak S, Pressler J, Rizvi T, Bogard M, et al. Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior. Cell Rep. 2017;19:545-557 pubmed publisher
    ..We thus identify Notch as an Nf1 effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1. ..
  36. Reyat J, Chimen M, Noy P, Szyroka J, Rainger G, Tomlinson M. ADAM10-Interacting Tetraspanins Tspan5 and Tspan17 Regulate VE-Cadherin Expression and Promote T Lymphocyte Transmigration. J Immunol. 2017;199:666-676 pubmed publisher
    ..Therefore endothelial Tspan5- and Tspan17-ADAM10 complexes may regulate inflammation by maintaining normal VE-cadherin expression and promoting T lymphocyte transmigration. ..
  37. Wang Z, Liu P, Liu X, Manfredsson F, Sandoval I, Yu S, et al. Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease. Mol Cell. 2017;67:812-825.e5 pubmed publisher
    ..Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis. ..
  38. Le T, Yim C, Park S, Katila N, Yang I, Song M, et al. Lodopyridones B and C from a marine sediment-derived bacterium Saccharomonospora sp. Bioorg Med Chem Lett. 2017;27:3123-3126 pubmed publisher
    ..Lodopyridones A-C show weak inhibitory activities on the ?-site amyloid precursor protein cleaving enzyme 1 (BACE1). ..
  39. Xu H, Xiao X, Hui Y, Zhang X, He Y, Li C, et al. Phenotype of 53 Chinese individuals with nicastrin gene mutations in association with familial hidradenitis suppurativa (acne inversa). Br J Dermatol. 2016;174:927-9 pubmed publisher
  40. Lokau J, Flynn C, Garbers C. Cleavage of the Interleukin-11 receptor induces processing of its C-terminal fragments by the gamma-secretase and the proteasome. Biochem Biophys Res Commun. 2017;491:296-302 pubmed publisher
  41. Wu C, Gudivada R, Aronow B, Jegga A. Computational drug repositioning through heterogeneous network clustering. BMC Syst Biol. 2013;7 Suppl 5:S6 pubmed publisher
  42. Inoshima N, Wang Y, Bubeck Wardenburg J. Genetic requirement for ADAM10 in severe Staphylococcus aureus skin infection. J Invest Dermatol. 2012;132:1513-6 pubmed publisher
  43. Mukherjee P, Pettersson M, Dutra J, Xie L, am Ende C. Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl Isostere. ChemMedChem. 2017;12:1574-1577 pubmed publisher
  44. Lownik J, Luker A, Damle S, Cooley L, El Sayed R, Hutloff A, et al. ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses. J Immunol. 2017;199:2305-2315 pubmed publisher
    ..Overall, we propose a novel regulation of the ICOS/ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL, as well as indirectly regulating ICOS, thus controlling ICOS/ICOSL-dependent responses. ..
  45. Yang W, Kim J, Han N, Lee E, Park S. 1,25-Dihydroxyvitamin D3 Attenuates the Effects of Lipopolysaccharide by Causing ADAM10-Dependent Ectodomain Shedding of Toll-Like Receptor 4. Cell Physiol Biochem. 2017;41:2104-2116 pubmed publisher
    ..1,25D3 causes ectodomain shedding of TLR4 and thereby decreases the responsiveness of cells to LPS. ADAM10, activated by extracellular Ca2+ influx, was implicated in the ectodomain cleavage of TLR4. ..
  46. Azimi S, Zonouzi A, Firuzi O, Iraji A, Saeedi M, Mahdavi M, et al. Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis. Eur J Med Chem. 2017;138:729-737 pubmed publisher
    ..These findings demonstrate that imidazopyridines-based compounds bearing phthalimide moiety have the potential to decrease amyloid-? levels and ameliorate the symptoms of Alzheimer's disease. ..
  47. Qin X, Wang Y, Paudel H. Inhibition of Early Growth Response 1 in the Hippocampus Alleviates Neuropathology and Improves Cognition in an Alzheimer Model with Plaques and Tangles. Am J Pathol. 2017;187:1828-1847 pubmed publisher
    ..Egr-1 regulates tau phosphorylation and A? synthesis in the brain by respectively controlling activities of Cdk5 and BACE-1, suggesting that Egr-1 is a potential therapeutic candidate for the treatment of AD. ..
  48. Rahimi Aliabadi S, Shahmohammadibeni N, Jamshidi J, Shandiz E, Mirfakhraie R, Ohadi M, et al. Association of ?-Secretase Functional Polymorphism with Risk of Schizophrenia. Genet Test Mol Biomarkers. 2017;21:248-251 pubmed publisher
    ..Our data indicate that rs490460 is associated with the risk of SZ. In silico analysis indicates that rs490460 may be a potential splicing site, which affects protein structure. Replication studies are needed to confirm our data. ..
  49. McRobb L, McKay M, Gamble J, Grace M, Moutrie V, Santos E, et al. Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence. Aging (Albany NY). 2017;9:1248-1268 pubmed publisher
    ..ADAM10 may be a key molecule linking radiation, senescence and endothelial dysfunction with increased risk of premature neurodegenerative diseases normally associated with aging. ..
  50. Duchatelet S, Miskinyte S, Join Lambert O, Ungeheuer M, Frances C, Nassif A, et al. First nicastrin mutation in PASH (pyoderma gangrenosum, acne and suppurative hidradenitis) syndrome. Br J Dermatol. 2015;173:610-2 pubmed publisher
  51. Faraco G, Park L, Zhou P, Luo W, Paul S, Anrather J, et al. Hypertension enhances A?-induced neurovascular dysfunction, promotes ?-secretase activity, and leads to amyloidogenic processing of APP. J Cereb Blood Flow Metab. 2016;36:241-52 pubmed
    ..We conclude that HTN enhances amyloidogenic APP processing, effects that may contribute to the pathogenic interaction between HTN and AD. ..
  52. Wagner S, Rynearson K, Duddy S, Zhang C, Nguyen P, Becker A, et al. Pharmacological and Toxicological Properties of the Potent Oral ?-Secretase Modulator BPN-15606. J Pharmacol Exp Ther. 2017;362:31-44 pubmed publisher
  53. Megra B, Eugenin E, Berman J. The Role of Shed PrPc in the Neuropathogenesis of HIV Infection. J Immunol. 2017;199:224-232 pubmed publisher
    ..We propose that shedding of PrPc could be a potential target for therapeutics to limit the cognitive impairment characteristic of neuroAIDS. ..