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Gene Review

BACE2  -  beta-site APP-cleaving enzyme 2

Homo sapiens

Synonyms: AEPLC, ALP56, ASP1, ASP21, Asp 1, ...
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Disease relevance of BACE2


Psychiatry related information on BACE2

  • BACE2 could be involved in the Alzheimer-like neuropathology of Down syndrome, as well as in Alzheimer's disease linked to chromosome 21 but not showing mutations in APP [6].
  • BACE2 appears to be associated with the early onset of dementia in patients with Down's syndrome, and it has been shown to be highly expressed in breast cancers [3].
  • Findings from clinical and duplex ultrasound scan (DU) examinations were compared with the CEAP classification, its adjunctive venous clinical severity score, and sensory thresholds [7].

High impact information on BACE2


Chemical compound and disease context of BACE2


Biological context of BACE2

  • BACE and BACE2 respond identically to conservative beta-site mutations, and alteration of a common active site Arg inhibits beta-site cleavage but not cleavage within Abeta by both enzymes [17].
  • However, a combined deficiency of BACE2 and BACE1 enhanced the bace1-/- lethality phenotype [1].
  • We investigated the role of endogenous BACE2 in A beta production in cells by selective inactivation of its transcripts using RNA interference [18].
  • We report the mRNA expression profile, DNA sequence, and molecular characterization of the BACE2 gene, located on chromosome 21q22 [19].
  • On either side of the proximal promoter region, two negative regulatory domains might reduce BACE2 expression under an induced condition [19].

Anatomical context of BACE2


Associations of BACE2 with chemical compounds


Physical interactions of BACE2


Enzymatic interactions of BACE2


Regulatory relationships of BACE2

  • This difficulty was confirmed by the finding that several potent memapsin 2 inhibitors effectively inhibited memapsin 1 as well [28].
  • When full-length Asp1(D110N) was expressed in COS-7 cells, it was not processed, suggesting that no other proteinase can activate Asp1 in these cells [24].
  • We conclude disruption of intramolecular hydrogen bonding between Thr18 and Asp21 enhances p53 transactivation by modulating Mdm-2 binding, facilitating TAF(II)31 recruitment [29].
  • This plasma renin form would be expected to be activated in association with the recently described renin/prorenin aspartyl protease receptor and to participate in local pathophysiological processes [30].

Other interactions of BACE2

  • These data suggest that BACE2 contributes to Abeta production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous [17].
  • Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice [1].
  • BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein [17].
  • Here we describe the characterization of a second highly related aspartic proteinase, Asp1 as a second beta-secretase candidate [21].
  • Aspartyl protease Cathepsin D (CTSD) has been suggested to play a role in the pathogenesis of sporadic Alzheimer's disease (AD) due to interference with protein degradation mechanisms [31].

Analytical, diagnostic and therapeutic context of BACE2

  • Though Sp1 can regulate both BACE1 and BACE2 genes, comparative sequence analysis and transcription factor prediction showed little similarity between the two promoters [20].
  • In addition, in situ hybridization of adult rat brain shows that BACE2 mRNA is expressed at very low levels in most brain regions [23].
  • To investigate whether BACE1 and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies [32].
  • Western blot analysis revealed no difference between DS and control in BACE-2 protein levels in the intracellular compartment [33].
  • The analysis revealed a 2.6-fold increase in BACE-2 mRNA levels in the DS group compared to the levels observed in the control group [33].


  1. 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]
  2. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome. Sun, X., He, G., Song, W. FASEB J. (2006) [Pubmed]
  3. Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. Ostermann, N., Eder, J., Eidhoff, U., Zink, F., Hassiepen, U., Worpenberg, S., Maibaum, J., Simic, O., Hommel, U., Gerhartz, B. J. Mol. Biol. (2006) [Pubmed]
  4. 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]
  5. A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene. Kondoh, K., Tsuji, N., Kamagata, C., Sasaki, M., Kobayashi, D., Yagihashi, A., Watanabe, N. Breast Cancer Res. Treat. (2003) [Pubmed]
  6. A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase. Solans, A., Estivill, X., de La Luna, S. Cytogenet. Cell Genet. (2000) [Pubmed]
  7. Does severe venous insufficiency have a different etiology in the morbidly obese? Is it venous? Padberg, F., Cerveira, J.J., Lal, B.K., Pappas, P.J., Varma, S., Hobson, R.W. J. Vasc. Surg. (2003) [Pubmed]
  8. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Selkoe, D., Kopan, R. Annu. Rev. Neurosci. (2003) [Pubmed]
  9. 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]
  10. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Wolfe, M.S., Xia, W., Ostaszewski, B.L., Diehl, T.S., Kimberly, W.T., Selkoe, D.J. Nature (1999) [Pubmed]
  11. 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]
  12. Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Haass, C., Steiner, H. Trends Cell Biol. (2002) [Pubmed]
  13. Down syndrome, Alzheimer's disease and seizures. Menéndez, M. Brain Dev. (2005) [Pubmed]
  14. Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1. Edbauer, D., Kaether, C., Steiner, H., Haass, C. J. Biol. Chem. (2004) [Pubmed]
  15. Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer's disease. Evin, G., Sharples, R.A., Weidemann, A., Reinhard, F.B., Carbone, V., Culvenor, J.G., Holsinger, R.M., Sernee, M.F., Beyreuther, K., Masters, C.L. Biochemistry (2001) [Pubmed]
  16. Dissociative inhibition of dimeric enzymes. Kinetic characterization of the inhibition of HIV-1 protease by its COOH-terminal tetrapeptide. Zhang, Z.Y., Poorman, R.A., Maggiora, L.L., Heinrikson, R.L., Kézdy, F.J. J. Biol. Chem. (1991) [Pubmed]
  17. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Farzan, M., Schnitzler, C.E., Vasilieva, N., Leung, D., Choe, H. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  18. 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]
  19. Characterization of the human beta-secretase 2 (BACE2) 5'-Flanking region: identification of a 268-bp region as the basal BACE2 promoter. Maloney, B., Ge, Y.W., Greig, N.H., Lahiri, D.K. J. Mol. Neurosci. (2006) [Pubmed]
  20. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. Sun, X., Wang, Y., Qing, H., Christensen, M.A., Liu, Y., Zhou, W., Tong, Y., Xiao, C., Huang, Y., Zhang, S., Liu, X., Song, W. FASEB J. (2005) [Pubmed]
  21. ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Hussain, I., Powell, D.J., Howlett, D.R., Chapman, G.A., Gilmour, L., Murdock, P.R., Tew, D.G., Meek, T.D., Chapman, C., Schneider, K., Ratcliffe, S.J., Tattersall, D., Testa, T.T., Southan, C., Ryan, D.M., Simmons, D.L., Walsh, F.S., Dingwall, C., Christie, G. Mol. Cell. Neurosci. (2000) [Pubmed]
  22. BACE2 functions as an alternative alpha-secretase in cells. Yan, R., Munzner, J.B., Shuck, M.E., Bienkowski, M.J. J. Biol. Chem. (2001) [Pubmed]
  23. Expression analysis of BACE2 in brain and peripheral tissues. Bennett, B.D., Babu-Khan, S., Loeloff, R., Louis, J.C., Curran, E., Citron, M., Vassar, R. J. Biol. Chem. (2000) [Pubmed]
  24. Prodomain processing of Asp1 (BACE2) is autocatalytic. Hussain, I., Christie, G., Schneider, K., Moore, S., Dingwall, C. J. Biol. Chem. (2001) [Pubmed]
  25. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Li, Y.M., Lai, M.T., Xu, M., Huang, Q., DiMuzio-Mower, J., Sardana, M.K., Shi, X.P., Yin, K.C., Shafer, J.A., Gardell, S.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  26. Processing of pulmonary surfactant protein B by napsin and cathepsin H. Ueno, T., Linder, S., Na, C.L., Rice, W.R., Johansson, J., Weaver, T.E. J. Biol. Chem. (2004) [Pubmed]
  27. Linear non-competitive inhibition of solubilized human gamma-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines. Tian, G., Sobotka-Briner, C.D., Zysk, J., Liu, X., Birr, C., Sylvester, M.A., Edwards, P.D., Scott, C.D., Greenberg, B.D. J. Biol. Chem. (2002) [Pubmed]
  28. 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]
  29. Mdm-2 binding and TAF(II)31 recruitment is regulated by hydrogen bond disruption between the p53 residues Thr18 and Asp21. Jabbur, J.R., Tabor, A.D., Cheng, X., Wang, H., Uesugi, M., Lozano, G., Zhang, W. Oncogene (2002) [Pubmed]
  30. Lectin chromatography of extrarenal renin protein in human plasma and tissues: potential endocrine function via the renin receptor. Stubbs, A.J., Skinner, S.L. Journal of the renin-angiotensin-aldosterone system : JRAAS. (2004) [Pubmed]
  31. Modulation of disease risk according to a cathepsin D / apolipoprotein E genotype in Parkinson's disease. Schulte, T., Böhringer, S., Schöls, L., Müller, T., Fischer, C., Riess, O., Przuntek, H., Berger, K., Epplen, J.T., Krüger, R. Journal of neural transmission (Vienna, Austria : 1996) (2003) [Pubmed]
  32. 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]
  33. BACE-2 is overexpressed in Down's syndrome. Barbiero, L., Benussi, L., Ghidoni, R., Alberici, A., Russo, C., Schettini, G., Pagano, S.F., Parati, E.A., Mazzoli, F., Nicosia, F., Signorini, S., Feudatari, E., Binetti, G. Exp. Neurol. (2003) [Pubmed]
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