Skip to main content
SpringerLink
Log in

BACE1 as a Therapeutic Target in Alzheimer’s Disease: Rationale and Current Status

  • Leading Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease of the central nervous system that causes dementia in a large percentage of the aged population and for which there are only symptomatic treatments. Disease-modifying therapies that are currently being pursued are based on the amyloid cascade theory. This states that accumulation of amyloid β (Aβ) in the brain triggers a cascade of cellular events leading to neurodegeneration. Aβ, which is the major constituent of amyloid plaques, is a peptidic fragment derived from proteolytic processing of the amyloid precursor protein (APP) by sequential cleavages that involve β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. Targeting BACE1 is a rational approach as its cleavage of APP is the rate-limiting step in Aβ production and this enzyme is elevated in the brain of patients with AD. Furthermore, knocking out the BACE1 gene in mice showed little apparent consequences. Ten years of intensive research has led to the design of efficacious BACE1 inhibitors with favorable pharmacological properties. Several drug candidates have shown promising results in animal models, as they reduce amyloid plaque pathology in the brain and rescue cognitive deficits. Phase I clinical trials indicate that these drugs are well tolerated, and the results from further trials in AD patients are now awaited eagerly. Yet, recent novel information on BACE1 biology, and the discovery that BACE1 cleaves a selection of substrates involved in myelination, retinal homeostasis, brain circuitry, and synaptic function, alert us to potential side effects of BACE1 inhibitors that will require further evaluation to provide a safe therapy for AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;377(9770):1019–31.

    Google Scholar 

  2. World Health Organization and Alzheimer’s Disease International. Dementia: a public health priority. Geneva: World Health Organization; 2012.

    Google Scholar 

  3. Masters CL, Beyreuther K. Alzheimer’s centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway. Brain. 2006;129(Pt 11):2823–39.

    PubMed  Google Scholar 

  4. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985;82(12):4245–9.

    PubMed  CAS  Google Scholar 

  5. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.

    PubMed  CAS  Google Scholar 

  6. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6.

    PubMed  CAS  Google Scholar 

  7. Mayeux R. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26:81–104.

    PubMed  CAS  Google Scholar 

  8. Hardy J. Testing times for the “amyloid cascade hypothesis”. Neurobiol Aging. 2002;23(6):1073–4.

    PubMed  Google Scholar 

  9. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10(9):698–712.

    PubMed  CAS  Google Scholar 

  10. Crouch PJ, Harding SM, White AR, Camakaris J, Bush AI, Masters CL. Mechanisms of a beta mediated neurodegeneration in Alzheimer’s disease. Int J Biochem Cell Biol. 2008;40(2):181–98.

    PubMed  CAS  Google Scholar 

  11. Armstrong RA. The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis”. Int J Alzheimers Dis. 2011;2011:630865.

    PubMed  CAS  Google Scholar 

  12. Lee HG, Zhu X, Castellani RJ, Nunomura A, Perry G, Smith MA. Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther. 2007;321(3):823–9.

    PubMed  CAS  Google Scholar 

  13. Goate A, Hardy J. Twenty years of Alzheimer’s disease-causing mutations. J Neurochem. 2012;120(Suppl 1):3–8.

    PubMed  CAS  Google Scholar 

  14. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357–67.

    PubMed  CAS  Google Scholar 

  15. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325(6106):733–6.

    PubMed  CAS  Google Scholar 

  16. Lazarov O, Demars MP. All in the family: how the APPs regulate neurogenesis. Front Neurosci. 2012;6:81.

    PubMed  CAS  Google Scholar 

  17. Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, et al. Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell. 2010;142(6):857–67.

    PubMed  CAS  Google Scholar 

  18. Kohli BM, Pflieger D, Mueller LN, Carbonetti G, Aebersold R, Nitsch RM, et al. Interactome of the amyloid precursor protein APP in brain reveals a protein network involved in synaptic vesicle turnover and a close association with Synaptotagmin-1. J Proteome Res. 2012;11(8):4075–90.

    PubMed  CAS  Google Scholar 

  19. Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, et al. Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci. 2009;29(35):10788–801.

    PubMed  CAS  Google Scholar 

  20. De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol. 2010;6(2):99–107.

    PubMed  Google Scholar 

  21. Creemers JW, Ines Dominguez D, Plets E, Serneels L, Taylor NA, Multhaup G, et al. Processing of beta-secretase by furin and other members of the proprotein convertase family. J Biol Chem. 2001;276(6):4211–7.

    PubMed  CAS  Google Scholar 

  22. Fandrich M. Oligomeric intermediates in amyloid formation: structure determination and mechanisms of toxicity. J Mol Biol. 2012;421(4–5):427–40.

    PubMed  Google Scholar 

  23. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488(7409):96–9.

    PubMed  CAS  Google Scholar 

  24. Kero M, Paetau A, Polvikoski T, Tanskanen M, Sulkava R, Jansson L, et al. Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol Aging. 2013;34(5):1518 e1–3.

    PubMed  Google Scholar 

  25. Cole SL, Vassar R. BACE1 structure and function in health and Alzheimer’s disease. Curr Alzheimer Res. 2008;5(2):100–20.

    PubMed  CAS  Google Scholar 

  26. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999;402(6761):537–40.

    PubMed  CAS  Google Scholar 

  27. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286(5440):735–41.

    PubMed  CAS  Google Scholar 

  28. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA. 2000;97(4):1456–60.

    PubMed  CAS  Google Scholar 

  29. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci. 1999;14(6):419–27.

    PubMed  CAS  Google Scholar 

  30. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature. 1999;402(6761):533–7.

    PubMed  CAS  Google Scholar 

  31. Haniu M, Denis P, Young Y, Mendiaz EA, Fuller J, Hui JO, et al. Characterization of Alzheimer’s beta -secretase protein BACE: a pepsin family member with unusual properties. J Biol Chem. 2000;275(28):21099–106.

    PubMed  CAS  Google Scholar 

  32. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000;290(5489):150–3.

    PubMed  CAS  Google Scholar 

  33. Qahwash I, He W, Tomasselli A, Kletzien RF, Yan R. Processing amyloid precursor protein at the beta-site requires proper orientation to be accessed by BACE1. J Biol Chem. 2004;279(37):39010–6.

    PubMed  CAS  Google Scholar 

  34. Yan R, Han P, Miao H, Greengard P, Xu H. The transmembrane domain of the Alzheimer’s beta-secretase (BACE1) determines its late Golgi localization and access to beta-amyloid precursor protein (APP) substrate. J Biol Chem. 2001;276(39):36788–96.

    PubMed  CAS  Google Scholar 

  35. Huse JT, Pijak DS, Leslie GJ, Lee VM, Doms RW. Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer’s disease beta-secretase. J Biol Chem. 2000;275(43):33729–37.

    PubMed  CAS  Google Scholar 

  36. Capell A, Steiner H, Willem M, Kaiser H, Meyer C, Walter J, et al. Maturation and pro-peptide cleavage of beta-secretase. J Biol Chem. 2000;275(40):30849–54.

    PubMed  CAS  Google Scholar 

  37. Bennett BD, Denis P, Haniu M, Teplow DB, Kahn S, Louis JC, et al. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s beta-secretase. J Biol Chem. 2000;275(48):37712–7.

    PubMed  CAS  Google Scholar 

  38. Benjannet S, Elagoz A, Wickham L, Mamarbachi M, Munzer JS, Basak A, et al. Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production. J Biol Chem. 2001;276(14):10879–87.

    PubMed  CAS  Google Scholar 

  39. Kandalepas PC, Vassar R. Identification and biology of beta-secretase. J Neurochem. 2012;120(Suppl 1):55–61.

    PubMed  CAS  Google Scholar 

  40. He X, Li F, Chang WP, Tang J. GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem. 2005;280(12):11696–703.

    PubMed  CAS  Google Scholar 

  41. He X, Chang WP, Koelsch G, Tang J. Memapsin 2 (beta-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2. FEBS Lett. 2002;524(1–3):183–7.

    PubMed  CAS  Google Scholar 

  42. von Arnim CA, Tangredi MM, Peltan ID, Lee BM, Irizarry MC, Kinoshita A, et al. Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy. J Cell Sci. 2004;117(Pt 22):5437–45.

    Google Scholar 

  43. Tan J, Evin G. Beta-site APP-cleaving enzyme 1 trafficking and Alzheimer’s disease pathogenesis. J Neurochem. 2012;120(6):869–80.

    PubMed  CAS  Google Scholar 

  44. Kang EL, Biscaro B, Piazza F, Tesco G. BACE1 endocytosis and trafficking are differentially regulated by ubiquitination at lysine 501 and the di-leucine motif in the C-terminus. J Biol Chem. 2012;287:42867–80.

    PubMed  CAS  Google Scholar 

  45. Kang EL, Cameron AN, Piazza F, Walker KR, Tesco G. Ubiquitin regulates GGA3-mediated degradation of BACE1. J Biol Chem. 2010;285(31):24108–19.

    PubMed  CAS  Google Scholar 

  46. Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, et al. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron. 2007;54(5):721–37.

    PubMed  CAS  Google Scholar 

  47. Santosa C, Rasche S, Barakat A, Bellingham SA, Ho M, Tan J, et al. Decreased expression of GGA3 protein in Alzheimer’s disease frontal cortex and increased co-distribution of BACE with the amyloid precursor protein. Neurobiol Dis. 2011;43(1):176–83.

    PubMed  CAS  Google Scholar 

  48. Schmechel A, Strauss M, Schlicksupp A, Pipkorn R, Haass C, Bayer TA, et al. Human BACE forms dimers and colocalizes with APP. J Biol Chem. 2004;279(38):39710–7.

    PubMed  CAS  Google Scholar 

  49. Westmeyer GG, Willem M, Lichtenthaler SF, Lurman G, Multhaup G, Assfalg-Machleidt I, et al. Dimerization of beta-site beta-amyloid precursor protein-cleaving enzyme. J Biol Chem. 2004;279(51):53205–12.

    PubMed  CAS  Google Scholar 

  50. Fleck D, Garratt AN, Haass C, Willem M. BACE1 dependent neuregulin proteolysis. Curr Alzheimer Res. 2012;9:178–83.

    PubMed  CAS  Google Scholar 

  51. Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol. 2002;51(6):783–6.

    PubMed  CAS  Google Scholar 

  52. Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci USA. 2008;105(17):6415–20.

    PubMed  CAS  Google Scholar 

  53. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002;59(9):1381–9.

    PubMed  Google Scholar 

  54. Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, et al. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med. 2003;9(1):3–4.

    PubMed  CAS  Google Scholar 

  55. Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA. 2004;101(10):3632–7.

    PubMed  CAS  Google Scholar 

  56. Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, et al. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008;14(7):723–30.

    PubMed  CAS  Google Scholar 

  57. Holsinger RM, McLean CA, Collins SJ, Masters CL, Evin G. Increased beta-Secretase activity in cerebrospinal fluid of Alzheimer’s disease subjects. Ann Neurol. 2004;55(6):898–9.

    PubMed  Google Scholar 

  58. Zhong Z, Ewers M, Teipel S, Burger K, Wallin A, Blennow K, et al. Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch Gen Psychiatry. 2007;64(6):718–26.

    PubMed  CAS  Google Scholar 

  59. Velanac V, Unterbarnscheidt T, Hinrichs W, Gummert MN, Fischer TM, Rossner MJ, et al. Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination. Glia. 2012;60(2):203–17.

    PubMed  Google Scholar 

  60. Ewers M, Cheng X, Nural HF, Walsh C, Meindl T, Teipel SJ, et al. Increased CSF- BACE1 activity associated with decreased hippocampus volume in Alzheimer’s disease. J Alzheimers Dis. 2011;25:373–81.

    PubMed  CAS  Google Scholar 

  61. Holsinger RM, Lee JS, Boyd A, Masters CL, Collins SJ. CSF BACE1 activity is increased in CJD and Alzheimer disease versus [corrected] other dementias. Neurology. 2006;67(4):710–2.

    PubMed  CAS  Google Scholar 

  62. Wu G, Sankaranarayanan S, Tugusheva K, Kahana J, Seabrook G, Shi XP, et al. Decrease in age-adjusted cerebrospinal fluid beta-secretase activity in Alzheimer’s subjects. Clin Biochem. 2008;41(12):986–96.

    PubMed  CAS  Google Scholar 

  63. Tamagno E, Guglielmotto M, Monteleone D, Tabaton M. Amyloid-beta production: major link between oxidative stress and BACE1. Neurotox Res. 2012;22(3):208–19.

    PubMed  CAS  Google Scholar 

  64. Chami L, Checler F. BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer’s disease. Mol Neurodegen. 2012;7:52.

    CAS  Google Scholar 

  65. O’Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, et al. Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron. 2008;60(6):988–1009.

    PubMed  Google Scholar 

  66. Velliquette RA, O’Connor T, Vassar R. Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer’s disease pathogenesis. J Neurosci. 2005;25(47):10874–83.

    PubMed  CAS  Google Scholar 

  67. Fukumoto H, Rosene DL, Moss MB, Raju S, Hyman BT, Irizarry MC. Beta-secretase activity increases with aging in human, monkey, and mouse brain. Am J Pathol. 2004;164(2):719–25.

    PubMed  CAS  Google Scholar 

  68. Tan J, Li QX, Ciccotosto G, Crouch PJ, Culvenor JG, White AR, et al. Mild oxidative stress induces redistribution of BACE1 in non-apoptotic conditions and promotes the amyloidogenic processing of Alzheimer’s disease amyloid precursor protein. PLoS One. 2013;8(4):e61246.

    PubMed  CAS  Google Scholar 

  69. Evin G, Barakat A, Masters CL. BACE: therapeutic target and potential biomarker for Alzheimer’s disease. Int J Biochem Cell Biol. 2010;42(12):1923–6.

    PubMed  CAS  Google Scholar 

  70. Vassar R, Kandalepas PC. The beta-secretase enzyme BACE1 as a therapeutic target for Alzheimer’s disease. Alzheimers Res Ther. 2011;3(3):20.

    PubMed  CAS  Google Scholar 

  71. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, et al. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet. 2001;10(12):1317–24.

    PubMed  CAS  Google Scholar 

  72. Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, et al. Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci. 2006;23(1):251–60.

    PubMed  Google Scholar 

  73. Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, et al. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis. 2007;26(1):134–45.

    PubMed  CAS  Google Scholar 

  74. Evin G, Lessene G, Wilkins S. BACE inhibitors as potential drugs for the treatment of Alzheimer’s disease: focus on bioactivity. Recent Pat CNS Drug Discov. 2011;6(2):91–106.

    PubMed  CAS  Google Scholar 

  75. Weiss MM, Williamson T, Babu-Khan S, Bartberger MD, Brown J, Chen K, et al. Design and preparation of a potent series of hydroxyethylamine containing beta-secretase inhibitors that demonstrate robust reduction of central beta-amyloid. J Med Chem. 2012;55(21):9009–24.

    PubMed  CAS  Google Scholar 

  76. Gerritz SW, Zhai W, Shi S, Zhu S, Toyn JH, Meredith JE Jr, et al. Acyl guanidine inhibitors of beta-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis. J Med Chem. 2012;55(21):9208–23.

    PubMed  CAS  Google Scholar 

  77. Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray J, Vajdos F, et al. Spirocyclic sulfamides as beta-secretase 1 (BACE-1) inhibitors for the treatment of Alzheimer’s disease: utilization of structure based drug design, WaterMap, and CNS penetration studies to identify centrally efficacious inhibitors. J Med Chem. 2012;55(21):9224–39.

    PubMed  CAS  Google Scholar 

  78. Swahn BM, Kolmodin K, Karlstrom S, von Berg S, Soderman P, Holenz J, et al. Design and synthesis of beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of beta-amyloid peptides. J Med Chem. 2012;55(21):9346–61.

    PubMed  CAS  Google Scholar 

  79. Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni SS, Xu X, Chang W, et al. Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2–P3-ligands. J Med Chem. 2007;50(10):2399–407.

    PubMed  CAS  Google Scholar 

  80. Ghosh AK, Brindisi M, Tang J. Developing β-secretase inhibitors for treatment of Alzheimer’s disease. J Neurochem. 2012;120:71–83.

    PubMed  CAS  Google Scholar 

  81. Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, et al. Beta-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J. 2011;25(2):775–84.

    PubMed  CAS  Google Scholar 

  82. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, et al. Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci. 2011;31(46):16507–16.

    PubMed  CAS  Google Scholar 

  83. Stachel SJ, Steele TG, Petrocchi A, Haugabook SJ, McGaughey G, Katharine Holloway M, et al. Discovery of pyrrolidine-based beta-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency. Bioorg Medl Chem Lett. 2012;22(1):240–4.

    CAS  Google Scholar 

  84. Treiber H, Hagemeyer N, Ehrenreich H, Simons M. BACE1 in central nervous system myelination revisited. Mol Psychiatry. 2012;17(3):237–9.

    PubMed  CAS  Google Scholar 

  85. Coburn CA, Stachel SJ, Li YM, Rush DM, Steele TG, Chen-Dodson E, et al. Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases. J Med Chem. 2004;47(25):6117–9.

    PubMed  CAS  Google Scholar 

  86. Steele TG, Hills ID, Nomland AA, de Leon P, Allison T, McGaughey G, et al. Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement. Bioorg Med Chem Lett. 2009;19(1):17–20.

    PubMed  CAS  Google Scholar 

  87. Mandal M, Zhu Z, Cumming JN, Liu X, Strickland C, Mazzola RD, et al. Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation. J Med Chem. 2012;55(21):9331–45.

    PubMed  CAS  Google Scholar 

  88. Jeppsson F, Eketjall S, Janson J, Karlstrom S, Gustavsson S, Olsson LL, et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012;287(49):41245–57.

    PubMed  CAS  Google Scholar 

  89. Huang H, La DS, Cheng AC, Whittington DA, Patel VF, Chen K, et al. Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimer’s disease. J Med Chem. 2012;55(21):9156–69.

    PubMed  CAS  Google Scholar 

  90. Mattsson N, Rajendran L, Zetterberg H, Gustavsson M, Andreasson U, Olsson M, et al. BACE1 inhibition induces a specific cerebrospinal fluid beta-amyloid pattern that identifies drug effects in the central nervous system. PLoS One. 2012;7(2):e31084.

    PubMed  CAS  Google Scholar 

  91. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006;314(5799):664–6.

    PubMed  CAS  Google Scholar 

  92. Li Q, Sudhof TC. Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1. J Biol Chem. 2004;279(11):10542–50.

    PubMed  CAS  Google Scholar 

  93. Fleck D, van Bebber F, Colombo A, Galante C, Schwenk BM, Rabe L, et al. Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci. 2013;33(18):7856–69.

    PubMed  CAS  Google Scholar 

  94. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9(12):1520–5.

    PubMed  CAS  Google Scholar 

  95. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008;9(6):437–52.

    PubMed  CAS  Google Scholar 

  96. Wen L, Lu Y-S, Zhu X-H, Li X-M, Woo R-S, Chen Y-J, et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA. 2009;107(3):1211–6.

    PubMed  Google Scholar 

  97. Pitcher GM, Kalia LV, Ng D, Goodfellow NM, Yee KT, Lambe EK, et al. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med. 2011;17(4):470–8.

    PubMed  CAS  Google Scholar 

  98. Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Hayashi-Takagi A, et al. Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci USA. 2010;107(12):5622–7.

    PubMed  CAS  Google Scholar 

  99. Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci USA. 2008;105(14):5585–90.

    PubMed  CAS  Google Scholar 

  100. Sankaranarayanan S, Price EA, Wu G, Crouthamel MC, Shi XP, Tugusheva K, et al. In vivo beta-secretase 1 inhibition leads to brain Abeta lowering and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1. J Pharmacol Exp Ther. 2008;324(3):957–69.

    PubMed  CAS  Google Scholar 

  101. Lichtenthaler SF, Dominguez DI, Westmeyer GG, Reiss K, Haass C, Saftig P, et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem. 2003;278(49):48713–9.

    PubMed  CAS  Google Scholar 

  102. Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, et al. Beta subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. J Biol Chem. 2005;280(24):23009–17.

    PubMed  CAS  Google Scholar 

  103. Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem. 2005;280(35):30797–806.

    PubMed  CAS  Google Scholar 

  104. Sachse CC, Kim YH, Agsten M, Huth T, Alzheimer C, Kovacs DM, et al. BACE1 and presenilin/gamma-secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage-gated potassium channels. FASEB J. 2013;27:2458–567.

    PubMed  CAS  Google Scholar 

  105. Eggert S, Paliga K, Soba P, Evin G, Masters CL, Weidemann A, et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation. J Biol Chem. 2004;279(18):18146–56.

    PubMed  CAS  Google Scholar 

  106. Kitazume S, Nakagawa K, Oka R, Tachida Y, Ogawa K, Luo Y, et al. In vivo cleavage of alpha 2,6-sialyltransferase by Alzheimer beta-secretase. J Biol Chem. 2005;280(9):8589–95.

    PubMed  CAS  Google Scholar 

  107. von Arnim CA, Kinoshita A, Peltan ID, Tangredi MM, Herl L, Lee BM, et al. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem. 2005;280(18):17777–85.

    Google Scholar 

  108. Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009;4(12):e8477.

    PubMed  Google Scholar 

  109. Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012;31(14):3157–68.

    PubMed  CAS  Google Scholar 

  110. Zhou L, Barao S, Laga M, Bockstael K, Borgers M, Gijsen H, et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem. 2012;287(31):25927–40.

    PubMed  CAS  Google Scholar 

  111. Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R. Beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem. 2012;287(46):38408–25.

    PubMed  CAS  Google Scholar 

  112. Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, et al. BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci. 2010;30(26):8819–29.

    PubMed  CAS  Google Scholar 

  113. Hitt BD, Jaramillo TC, Chetkovich DM, Vassar R. BACE1−/− mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization. Mol Neurodegener. 2010;5:31.

    PubMed  Google Scholar 

  114. Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci. 2005;25(50):11693–709.

    PubMed  CAS  Google Scholar 

  115. Wang H, Song L, Laird F, Wong PC, Lee HK. BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus. J Neurosci. 2008;28(35):8677–81.

    PubMed  CAS  Google Scholar 

  116. Cai J, Qi X, Kociok N, Skosyrski S, Emilio A, Ruan Q, et al. β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med. 2012;4(9):980–91.

    PubMed  CAS  Google Scholar 

  117. Corbett BF, Leiser SC, Ling H-P, Nagy R, Breysse N, Zhang X, et al. Sodium channel cleavage is associated with aberrant neuronal activity and cognitive deficits in a mouse model of Alzheimer’s disease. J Neurosci. 2013;33(16):7020–6.

    PubMed  CAS  Google Scholar 

  118. Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol. 2008;6(10):e257.

    PubMed  Google Scholar 

  119. Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T, Hirode M, et al. A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer’s disease. J Neurosci. 2010;30(33):11157–66.

    PubMed  CAS  Google Scholar 

  120. Zhou L, Chavez-Gutierrez L, Bockstael K, Sannerud R, Annaert W, May PC, et al. Inhibition of beta-secretase in vivo via antibody binding to unique loops (D and F) of BACE1. J Biol Chem. 2011;286(10):8677–87.

    PubMed  CAS  Google Scholar 

  121. Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci Transl Med. 2011;3(84):84ra43.

    PubMed  Google Scholar 

  122. Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011;3(84):84ra44.

    PubMed  Google Scholar 

  123. Kao SC, Krichevsky AM, Kosik KS, Tsai LH. BACE1 suppression by RNA interference in primary cortical neurons. J Biol Chem. 2004;279(3):1942–9.

    PubMed  CAS  Google Scholar 

  124. Singer O, Marr RA, Rockenstein E, Crews L, Coufal NG, Gage FH, et al. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci. 2005;8(10):1343–9.

    PubMed  CAS  Google Scholar 

  125. Peng KA, Masliah E. Lentivirus-expressed siRNA vectors against Alzheimer disease. Methods Mol Biol. 2010;614:215–24.

    PubMed  CAS  Google Scholar 

  126. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–5.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors acknowledge funding support from the Judith Jane Mason and Harold Stannett Williams Memorial Foundation. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia

    Genevieve Evin & Christopher Hince

  2. Oxidation Biology Laboratory, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC, 3010, Australia

    Genevieve Evin

Authors
  1. Genevieve Evin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Hince
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Genevieve Evin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Evin, G., Hince, C. BACE1 as a Therapeutic Target in Alzheimer’s Disease: Rationale and Current Status. Drugs Aging 30, 755–764 (2013). https://doi.org/10.1007/s40266-013-0099-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-013-0099-3

Keywords

Search

Navigation