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Gene Review

BACE1  -  beta-site APP-cleaving enzyme 1

Homo sapiens

Synonyms: ASP2, Asp 2, Aspartyl protease 2, BACE, Beta-secretase 1, ...
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Disease relevance of BACE1


Psychiatry related information on BACE1

  • BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease [7].
  • Here we show that BACE1 null mice engineered to overexpress human APP (BACE1(-/-).Tg2576(+)) are rescued from Abeta-dependent hippocampal memory deficits [7].
  • Highlights of the conference included reports on brain imaging, the discovery of mutations in the progranulin gene that cause frontotemporal dementia, the finding that neuregulin-1 is a substrate for BACE1 and new interest in the connection between Alzheimer's disease and metabolic syndromes [8].
  • Endogenous beta2 processing and Na(v)1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels [9].

High impact information on BACE1

  • Our data support a mechanism by which reticulon proteins block access of BACE1 to amyloid precursor protein and reduce the cleavage of this protein [10].
  • Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the beta-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden [11].
  • Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease involved in the production of beta-amyloid peptide in Alzheimer's disease and is a major target for drug design [12].
  • The active site of memapsin 2 is more open and less hydrophobic than that of other human aspartic proteases [12].
  • Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase [13].

Chemical compound and disease context of BACE1


Biological context of BACE1


Anatomical context of BACE1

  • Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action [24].
  • Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle; (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers; and (c) are immunoreactive in necrotizing muscle fibers [25].
  • We show that the levels of exogenous and endogenous mature BACE1 expressed in presenilin-deficient mouse embryonic fibroblasts (PS-/-MEFs) were reduced significantly compared to those in wild-type MEFs [1].
  • In transfected cells both BACE1A, which encodes the originally described full-length BACE1 protein and the close homolog BACE2 localized mainly to post-Golgi membranes [26].
  • Here, we demonstrate that BACE1 binds to nicastrin, a component of gamma-secretase complexes, in vitro, and that nicastrin activates beta-secretase activity in COS-7 cells [27].

Associations of BACE1 with chemical compounds

  • We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates [24].
  • Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's beta-secretase [24].
  • Pulse-chase and time-course degradation experiments showed that ceramide post-translationally stabilizes the beta-secretase BACE1 [14].
  • While PB2-T1 shares similar substrate specificities with BACE1 and other 'general' aspartic proteases, the specificity of PB2-T2 is more constrained, apparently preferring to cleave at the NH2-terminal side of paired basic residues [28].
  • The BACE1 protein level was increased in a time- and dosage-dependent manner in the inducible BACE1 stable cells by treatment with inducer ponasterone A [29].
  • We used an alternate strategy to explore the function of BACE1 in membrane microdomains without altering the cellular cholesterol level [30].

Physical interactions of BACE1


Enzymatic interactions of BACE1

  • Recombinant memapsin 2 specifically hydrolyzed peptides derived from the beta-secretase site of both the wild-type and Swedish mutant beta-amyloid precursor protein (APP) with over 60-fold increase of catalytic efficiency for the latter [2].
  • Recombinant memapsin 2 also cleaved a peptide derived from the processing site of presenilin 1, albeit with poor kinetic efficiency [2].
  • The amyloid precursor protein is cleaved within its ectodomain by beta-amyloid-converting enzyme (BACE) yielding C99, which is further cleaved by gamma-secretase within its putative transmembrane domain (TMD) [33].
  • Recent reports show that furin cleaves the pro-peptide of ASP-2, whereas ASP-1 undergoes auto-catalysis [34].
  • We found that BACE1 cleaved polysialyltransferase ST8Sia IV (PST) in vitro [35].

Co-localisations of BACE1


Regulatory relationships of BACE1

  • This difficulty was confirmed by the finding that several potent memapsin 2 inhibitors effectively inhibited memapsin 1 as well [37].
  • Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing [24].
  • Novel mutations introduced at the beta-site of amyloid beta protein precursor enhance the production of amyloid beta peptide by BACE1 in vitro and in cells [38].
  • Here, we show that GGA1 regulates the retrograde transport of internalized BACE1 from endosomal compartments to the TGN by direct interaction in a phosphorylation-dependent manner [39].
  • Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates the transcription of BACE1 as well as inflammatory responses in the brain and atherosclerotic risk factors known to be involved also in AD [40].

Other interactions of BACE1

  • These and other results suggest that memapsin 2 fits all of the criteria of beta-secretase, which catalyzes the rate-limiting step of the in vivo production of the beta-amyloid (Abeta) peptide leading to the progression of Alzheimer's disease [2].
  • Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice [21].
  • A crystal structure of the complex between memapsin 2 phosphoserine peptide and GGA1 VHS was solved at 2.6 A resolution [41].
  • These observations suggest that the endocytosis and intracellular transport of memapsin 2, mediated by its cytosolic domain, may involve the binding of GGA1 and GGA2 [42].
  • However,when we combined our results with those previously reported, a clear increase of the risk to develop AD appeared in subjects carrying both the BACE1 exon 5 GG genotype and the APOE epsilon4-allele (crude OR = 2.2, P = 0.004) [43].

Analytical, diagnostic and therapeutic context of BACE1




  1. Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). Kuzuya, A., Uemura, K., Kitagawa, N., Aoyagi, N., Kihara, T., Ninomiya, H., Ishiura, S., Takahashi, R., Shimohama, S. J. Neurosci. Res. (2007) [Pubmed]
  2. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A., Tang, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  3. Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis. Vattemi, G., Engel, W.K., McFerrin, J., Buxbaum, J.D., Pastorino, L., Askanas, V. Lancet (2001) [Pubmed]
  4. Alzheimer's disease beta-secretase BACE1 is not a neuron-specific enzyme. Rossner, S., Lange-Dohna, C., Zeitschel, U., Perez-Polo, J.R. J. Neurochem. (2005) [Pubmed]
  5. Hypoxia and reoxygenation increased BACE1 mRNA and protein levels in human neuroblastoma SH-SY5Y cells. Xue, S., Jia, L., Jia, J. Neurosci. Lett. (2006) [Pubmed]
  6. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Holsinger, R.M., McLean, C.A., Beyreuther, K., Masters, C.L., Evin, G. Ann. Neurol. (2002) [Pubmed]
  7. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Ohno, M., Sametsky, E.A., Younkin, L.H., Oakley, H., Younkin, S.G., Citron, M., Vassar, R., Disterhoft, J.F. Neuron (2004) [Pubmed]
  8. Las noticias de Madrid (News from Madrid). Wahrle, S.E. Molecular neurodegeneration [electronic resource]. (2006) [Pubmed]
  9. BACE1 regulates voltage-gated sodium channels and neuronal activity. Kim, D.Y., Carey, B.W., Wang, H., Ingano, L.A., Binshtok, A.M., Wertz, M.H., Pettingell, W.H., He, P., Lee, V.M., Woolf, C.J., Kovacs, D.M. Nat. Cell Biol. (2007) [Pubmed]
  10. Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. He, W., Lu, Y., Qahwash, I., Hu, X.Y., Chang, A., Yan, R. Nat. Med. (2004) [Pubmed]
  11. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Yan, R., Bienkowski, M.J., Shuck, M.E., Miao, H., Tory, M.C., Pauley, A.M., Brashier, J.R., Stratman, N.C., Mathews, W.R., Buhl, A.E., Carter, D.B., Tomasselli, A.G., Parodi, L.A., Heinrikson, R.L., Gurney, M.E. Nature (1999) [Pubmed]
  12. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Hong, L., Koelsch, G., Lin, X., Wu, S., Terzyan, S., Ghosh, A.K., Zhang, X.C., Tang, J. Science (2000) [Pubmed]
  13. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M.A., Biere, A.L., Curran, E., Burgess, T., Louis, J.C., Collins, F., Treanor, J., Rogers, G., Citron, M. Science (1999) [Pubmed]
  14. Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis. Puglielli, L., Ellis, B.C., Saunders, A.J., Kovacs, D.M. J. Biol. Chem. (2003) [Pubmed]
  15. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Cordy, J.M., Hussain, I., Dingwall, C., Hooper, N.M., Turner, A.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  16. Heparin activates beta-secretase (BACE1) of Alzheimer's disease and increases autocatalysis of the enzyme. Beckman, M., Holsinger, R.M., Small, D.H. Biochemistry (2006) [Pubmed]
  17. Stereoselective synthesis of constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: dipolar cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone carboxylic acids. Hanessian, S., Yun, H., Hou, Y., Tintelnot-Blomley, M. J. Org. Chem. (2005) [Pubmed]
  18. Characterization of Drosophila aspartic proteases that induce the secretion of a Golgi-resident transferase, heparan sulfate 6-O-sulfotransferase. Kotani, N., Kitazume, S., Kamimura, K., Takeo, S., Aigaki, T., Nakato, H., Hashimoto, Y. J. Biochem. (2005) [Pubmed]
  19. Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Christensen, M.A., Zhou, W., Qing, H., Lehman, A., Philipsen, S., Song, W. Mol. Cell. Biol. (2004) [Pubmed]
  20. Antagonistic effects of beta-site amyloid precursor protein-cleaving enzymes 1 and 2 on beta-amyloid peptide production in cells. Basi, G., Frigon, N., Barbour, R., Doan, T., Gordon, G., McConlogue, L., Sinha, S., Zeller, M. J. Biol. Chem. (2003) [Pubmed]
  21. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. Dominguez, D., Tournoy, J., Hartmann, D., Huth, T., Cryns, K., Deforce, S., Serneels, L., Camacho, I.E., Marjaux, E., Craessaerts, K., Roebroek, A.J., Schwake, M., D'Hooge, R., Bach, P., Kalinke, U., Moechars, D., Alzheimer, C., Reiss, K., Saftig, P., De Strooper, B. J. Biol. Chem. (2005) [Pubmed]
  22. Altered amyloid-beta metabolism and deposition in genomic-based beta-secretase transgenic mice. Chiocco, M.J., Kulnane, L.S., Younkin, L., Younkin, S., Evin, G., Lamb, B.T. J. Biol. Chem. (2004) [Pubmed]
  23. Down-regulation of muscarinic acetylcholine receptor M2 adversely affects the expression of Alzheimer's disease-relevant genes and proteins. Zuchner, T., Schliebs, R., Perez-Polo, J.R. J. Neurochem. (2005) [Pubmed]
  24. Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's beta-secretase. Scholefield, Z., Yates, E.A., Wayne, G., Amour, A., McDowell, W., Turnbull, J.E. J. Cell Biol. (2003) [Pubmed]
  25. BACE1 and BACE2 in pathologic and normal human muscle. Vattemi, G., Engel, W.K., McFerrin, J., Pastorino, L., Buxbaum, J.D., Askanas, V. Exp. Neurol. (2003) [Pubmed]
  26. Splice variants of the beta-site APP-cleaving enzyme BACE1 in human brain and pancreas. Ehehalt, R., Michel, B., De Pietri Tonelli, D., Zacchetti, D., Simons, K., Keller, P. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  27. BACE1 interacts with nicastrin. Hattori, C., Asai, M., Oma, Y., Kino, Y., Sasagawa, N., Saido, T.C., Maruyama, K., Ishiura, S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  28. Enzymic properties of recombinant BACE2. Kim, Y.T., Downs, D., Wu, S., Dashti, A., Pan, Y., Zhai, P., Wang, X., Zhang, X.C., Lin, X. Eur. J. Biochem. (2002) [Pubmed]
  29. Control of APP processing and Abeta generation level by BACE1 enzymatic activity and transcription. Li, Y., Zhou, W., Tong, Y., He, G., Song, W. FASEB J. (2006) [Pubmed]
  30. Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts. Vetrivel, K.S., Meckler, X., Chen, Y., Nguyen, P.D., Seidah, N.G., Vassar, R., Wong, P.C., Fukata, M., Kounnas, M.Z., Thinakaran, G. J. Biol. Chem. (2009) [Pubmed]
  31. Functional characterization of the 5' flanking region of the BACE gene: identification of a 91 bp fragment involved in basal level of BACE promoter expression. Ge, Y.W., Maloney, B., Sambamurti, K., Lahiri, D.K. FASEB J. (2004) [Pubmed]
  32. Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase. Sauder, J.M., Arthur, J.W., Dunbrack, R.L. J. Mol. Biol. (2000) [Pubmed]
  33. The transmembrane domain of the amyloid precursor protein in microsomal membranes is on both sides shorter than predicted. Grziwa, B., Grimm, M.O., Masters, C.L., Beyreuther, K., Hartmann, T., Lichtenthaler, S.F. J. Biol. Chem. (2003) [Pubmed]
  34. Pro-domain removal in ASP-2 and the cleavage of the amyloid precursor are influenced by pH. Sidera, C., Liu, C., Austen, B. BMC Biochem. (2002) [Pubmed]
  35. Screening a series of sialyltransferases for possible BACE1 substrates. Kitazume, S., Tachida, Y., Oka, R., Nakagawa, K., Takashima, S., Lee, Y.C., Hashimoto, Y. Glycoconj. J. (2006) [Pubmed]
  36. Human BACE forms dimers and colocalizes with APP. Schmechel, A., Strauss, M., Schlicksupp, A., Pipkorn, R., Haass, C., Bayer, T.A., Multhaup, G. J. Biol. Chem. (2004) [Pubmed]
  37. Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity. Turner, R.T., Loy, J.A., Nguyen, C., Devasamudram, T., Ghosh, A.K., Koelsch, G., Tang, J. Biochemistry (2002) [Pubmed]
  38. Novel mutations introduced at the beta-site of amyloid beta protein precursor enhance the production of amyloid beta peptide by BACE1 in vitro and in cells. Shi, X.P., Tugusheva, K., Bruce, J.E., Lucka, A., Chen-Dodson, E., Hu, B., Wu, G.X., Price, E., Register, R.B., Lineberger, J., Miller, R., Tang, M.J., Espeseth, A., Kahana, J., Wolfe, A., Crouthamel, M.C., Sankaranarayanan, S., Simon, A., Chen, L., Lai, M.T., Pietrak, B., DiMuzio, J., Li, Y., Xu, M., Huang, Q., Garsky, V., Sardana, M.K., Hazuda, D.J. J. Alzheimers Dis. (2005) [Pubmed]
  39. GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network. Wahle, T., Prager, K., Raffler, N., Haass, C., Famulok, M., Walter, J. Mol. Cell. Neurosci. (2005) [Pubmed]
  40. Association analysis of peroxisome proliferator-activated receptor gamma polymorphisms and late onset Alzheimer's disease in the finnish population. Koivisto, A.M., Helisalmi, S., Pihlajamaki, J., Hiltunen, M., Koivisto, K., Moilanen, L., Kuusisto, J., Helkala, E.L., Hanninen, T., Kervinen, K., Kesaniemi, Y.A., Laakso, M., Soininen, H. Dementia and geriatric cognitive disorders (2006) [Pubmed]
  41. Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins. He, X., Zhu, G., Koelsch, G., Rodgers, K.K., Zhang, X.C., Tang, J. Biochemistry (2003) [Pubmed]
  42. Memapsin 2 (beta-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2. He, X., Chang, W.P., Koelsch, G., Tang, J. FEBS Lett. (2002) [Pubmed]
  43. Association study between Alzheimer's disease and genes involved in Abeta biosynthesis, aggregation and degradation: suggestive results with BACE1. Clarimón, J., Bertranpetit, J., Calafell, F., Boada, M., Tàrraga, L., Comas, D. J. Neurol. (2003) [Pubmed]
  44. PAR-4 is involved in regulation of beta-secretase cleavage of the Alzheimer amyloid precursor protein. Xie, J., Guo, Q. J. Biol. Chem. (2005) [Pubmed]
  45. Development of BACE1 inhibitors for Alzheimer's disease. Guo, T., Hobbs, D.W. Current medicinal chemistry. (2006) [Pubmed]
  46. Beta-site APP cleaving enzyme 1 (BACE1) is increased in remaining neurons in Alzheimer's disease brains. Harada, H., Tamaoka, A., Ishii, K., Shoji, S., Kametaka, S., Kametani, F., Saito, Y., Murayama, S. Neurosci. Res. (2006) [Pubmed]
  47. Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer's disease pathogenesis. Velliquette, R.A., O'Connor, T., Vassar, R. J. Neurosci. (2005) [Pubmed]
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