Secretases as Pharmacological Targets in Alzheimer's Disease

  • Nigel M. Hooper
  • Emma R. L. C. Vardy

Alzheimer’s disease (AD) is the major neurodegenerative disease of the aging brain and, whereas the underlying pathology remains extremely complex and poorly understood, poses an ever-expanding burden on health services in the context of an aging population. By 2010, it is estimated that there will be half a million AD sufferers in the UK, while currently there are greater than 12 million sufferers worldwide. AD is characterized by a decline in cognitive function that progresses slowly, leaving patients in the later stages of the illness bedridden, incontinent, and dependent on custodial care, with death occurring, on average, 9 years after diagnosis. Although there are currently a few drugs used to help manage the cognitive effects of AD, namely the acetylcholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine, there is presently no available therapy to arrest or modify the progress of the disease (Vardy, Catto, & Hooper, 2005).


Lipid Raft Amyloid Precursor Protein Amyloidogenic Pathway Alzheimer Amyloid Precursor Protein Notch Cleavage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abad-Rodriguez, J., Ledesma, M. D., Craessaerts, K., Perga, S., Medina, M., Delacourte, A., et al. (2004). Neuronal membrane cholesterol loss enhances amyloid peptide generation. The Journal of Cell Biology, 167, 953–960.CrossRefPubMedGoogle Scholar
  2. Allinson, T. M., Parkin, E. T., Condon, T. P., Schwager, S. L., Sturrock, E. D., Turner, A. J., et al. (2004). The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein. European Journal of Biochemistry, 271, 2539–2547.CrossRefPubMedGoogle Scholar
  3. Allinson, T. M., Parkin, E. T., Turner, A. J., & Hooper, N. M. (2003). ADAMs family members as amyloid precursor protein alpha-secretases. Journal of Neuroscience Research, 74, 342–352.CrossRefPubMedGoogle Scholar
  4. Andersen, O. M., Reiche, J., Schmidt, V., Gotthardt, M., Spoelgen, R., Behlke, J., et al. (2005). Neuronal sorting protein-related receptor sorLA/lr11 regulates processing of the amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America, 102, 13461–13466.CrossRefPubMedGoogle Scholar
  5. Arbel, M., Yacoby, I., & Solomon, B. (2005). Inhibition of amyloid precursor protein processing by beta-secretase through site-directed antibodies. Proceedings of the National Academy of Sciences of the United States of America, 102, 7718–7723.CrossRefPubMedGoogle Scholar
  6. von Arnim, C. A. F., Kinoshita, A., Peltan, I. D., Tangredi, M. M., Herl, L., Lee, B. M., et al. (2005). The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. The Journal of Biological Chemistry, 280, 17777–17785.CrossRefGoogle Scholar
  7. Artavanis-Tsakonas, S., Matsuno, K., & Fortini, M. E. (1995). Notch signalling. Science, 268, 225–232.CrossRefPubMedGoogle Scholar
  8. Asai, M., Hattori, C., Iwata, N., Saido, T. C., Sasagawa, N., Szabo, B., et al. (2006). The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice. Journal of Neurochemistry., 96, 533–540.CrossRefPubMedGoogle Scholar
  9. Barger, S. W., & Harmon, A. D. (1997). Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature, 388, 878–881.CrossRefPubMedGoogle Scholar
  10. Beher, D., Clarke, E. E., Wrigley, J. D., Martin, A. C., Nadin, A., Churcher, I., et al. (2004). Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism. The Journal of Biological Chemistry, 279, 43419–43426.CrossRefPubMedGoogle Scholar
  11. Brown, D. A., & London, E. (1998). Functions of lipid rafts in biological membranes. Annual Review of Cell and Developmental Biology, 14, 111–136.CrossRefPubMedGoogle Scholar
  12. Buxbaum, J. D., Liu, K. N., Luo, Y., Slack, J. L., Stocking, K. L., Peschon, J. J., et al. (1998). Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. The Journal of Biological Chemistry, 273, 27765–27767.CrossRefPubMedGoogle Scholar
  13. Cai, J., Jiang, W. G., Grant, M. B., & Boulton, M. (2006). Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1. The Journal of Biological Chemistry, 281, 3604–3613.CrossRefPubMedGoogle Scholar
  14. Cai, H., Wang, Y., McCarthy, D., Wen, H., Borchelt, D. R., Price, D. L., et al. C. (2001). BACE1 is the major beta-secretase for generation of Aβ peptides by neurons. Nature Neuroscience, 4, 233–234.CrossRefPubMedGoogle Scholar
  15. Caporaso, G. L., Gandy, S. E., Buxbaum, J. D., Ramabhadran, T. V., & Greengard, P. (1992). Protein phosphorylation regulates secretion of Alzheimer β/A4 amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America, 89, 3055–3059.CrossRefPubMedGoogle Scholar
  16. Chang, W. P., Koelsch, G., Wong, S., Downs, D., Da, H., Weerasena, V., et al. (2004). In vivo inhibition of Aβ production by memapsin 2 (beta-secretase) inhibitors. Journal of Neurochemistry, 89, 1409–1416.CrossRefPubMedGoogle Scholar
  17. Citron, M. (2004a). Beta-secretase inhibition for the treatment of Alzheimer's disease–promise and challenge. Trends in pharmacological sciences, 25, 92–97.CrossRefPubMedGoogle Scholar
  18. Citron, M. (2004b). Strategies for disease modification in Alzheimer's disease. Nature Reviews. Neuroscience, 5, 677–685.CrossRefPubMedGoogle Scholar
  19. Cleary, J. P., Walsh, D. M., Hofmeister, J. J., Shankar, G. M., Kuskowski, M. A., Selkoe, D. J., et al. (2005). Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nature Neuroscience, 8, 79–84.CrossRefPubMedGoogle Scholar
  20. Cordy, J. M., Hooper, N. M., & Turner, A. J. (2006). The involvement of lipid rafts in Alzheimer's disease. Molecular Membrane Biology, 23, 111–122.CrossRefPubMedGoogle Scholar
  21. Cordy, J. M., Hussain, I., Dingwall, C., Hooper, N. M., & Turner, A. J. (2003). Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America, 100, 11735–11740.CrossRefPubMedGoogle Scholar
  22. Cowan, J. W., Wang, X., Guan, R., He, K., Jiang, J., Baumann, G., et al. (2005). Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage. The Journal of Biological Chemistry, 280, 19331–19342.CrossRefPubMedGoogle Scholar
  23. Dewachter, I., & Van Leuven, F. (2002). Secretases as targets for the treatment of Alzheimer's disease: The prospects. Lancet Neurology, 1, 409–416.CrossRefPubMedGoogle Scholar
  24. Ehehalt, R., Keller, P., Haass, C., Thiele, C., & Simons, K. (2003). Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. Journal of Cell Biology, 160, 113–123.CrossRefPubMedGoogle Scholar
  25. Esler, W. P., & Wolfe, M. S. (2001). A portrait of Alzheimer secretases—new features and familiar faces. Science, 293, 1449–1454.CrossRefPubMedGoogle Scholar
  26. Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., et al. (2001). Simvastatin strongly reduces levels of Alzheimer's disease beta - amyloid peptides Aβ 42 and Aβ 40 in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 98, 5856–5861.CrossRefPubMedGoogle Scholar
  27. Francis, P. T., Nordberg, A., & Arnold, S. E. (2005). A preclinical view of cholinesterase inhibitors in neuroprotection: Do they provide more than symptomatic benefits in Alzheimer's disease? Trends in Pharmacological Sciences, 26, 104–111.CrossRefPubMedGoogle Scholar
  28. Fukumoto, H., Cheung, B. S., Hyman, B. T., & Irizarry, M. C. (2002). Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Archives of Neurology, 59, 1381–1389.CrossRefPubMedGoogle Scholar
  29. Haass, C. (2004). Take five-BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation. The EMBO Journal, 23, 483–488.CrossRefPubMedGoogle Scholar
  30. Haass, C., & Steiner, H. (2002). Alzheimer disease gamma-secretase: A complex story of GXGD-type presenilin proteases. Trends in Cell Biology, 12, 556–562.CrossRefPubMedGoogle Scholar
  31. He, W., Lu, Y., Qahwash, I., Hu, X. Y., Chang, A., & Yan, R. (2004). Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nature Medicine, 10, 959–965.CrossRefPubMedGoogle Scholar
  32. Hong, L., Koelsch, G., Lin, X., Wu, S., Terzyan, S., Ghosh, A. K., et al. (2000). Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science, 290, 150–153.CrossRefPubMedGoogle Scholar
  33. Hooper, N. M. (1999). Detergent-insoluble glycosphingolipid/cholesterol-rich membrane domains, lipid rafts and caveolae. Molecular Membrane Biology, 16, 145–156.CrossRefPubMedGoogle Scholar
  34. Hooper, N. M., & Turner, A. J. (2002). The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer s disease. Current Medicinal Chemistry, 9, 1107–1119.PubMedGoogle Scholar
  35. Hung, A. Y., Haass, C., Nitsch, R. M., Qiu, W. Q., Citron, M., Wurtman, R. J., et al. (1993). Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. The Journal of Biological Chemistry, 268, 22959–22962.PubMedGoogle Scholar
  36. Hussain, I. (2004). The potential for BACE1 inhibitors in the treatment of Alzheimer's disease. The Investigational Drugs Journal, 7, 653–658.Google Scholar
  37. Kaether, C., & Haass, C. (2004). A lipid boundary separates APP and secretases and limits amyloid beta-peptide generation. Journal of Cell Biology, 167, 809–812.CrossRefPubMedGoogle Scholar
  38. Kim, D. Y., Ingano, L. A. M., Carey, B. W., Pettingell, W. H., & Kovacs, D. M. (2005). Presenilin/gamma-secretase-mediated cleavage of the voltage-gated sodium channel beta2-subunit regulates cell adhesion and migration. The Journal of Biological Chemistry, 280, 23251–23261.CrossRefPubMedGoogle Scholar
  39. Kitazume, S., Nakagawa, K., Oka, R., Tachida, Y., Ogawa, K., Luo, Y., et al. (2005). In vivo cleavage of alpha2, 6-sialyltransferase by Alzheimer beta-secretase. The Journal of Biological Chemistry, 280, 8589–8595.CrossRefPubMedGoogle Scholar
  40. Kojro, E., Gimpl, G., Lammich, S., Marz, W., & Fahrenholz, F. (2001). Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proceedings of the National Academy of Sciences of the United States of America, 98, 5815–5820.CrossRefPubMedGoogle Scholar
  41. Kojro, E., Postina, R., Buro, C., Meiringer, C., Gehrig-Burger, K., & Fahrenholz, F. (2006). The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. The FASEB Journal, 20, 512–514.PubMedGoogle Scholar
  42. LaFerla, F. M., & Oddo, S. (2005). Alzheimer's disease: Aβ, tau and synaptic dysfunction. Trends in Molecular Medicine., 11, 170–176.CrossRefPubMedGoogle Scholar
  43. Lannfelt, L., Basun, H., Wahlund, L. O., Rowe, B. A., & Wagner, S. L. (1995). Decreased α-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer's disease. Nature Medicine, 1, 829–832.CrossRefPubMedGoogle Scholar
  44. Lesne, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., et al. (2006). A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440, 352–357.CrossRefPubMedGoogle Scholar
  45. Li, R., Lindholm, K., Yang, L. B., Yue, X., Citron, M., Yan, R., et al. (2004). Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients. Proceedings of the National Academy of Sciences of the United States of America, 101, 3632–3637.CrossRefPubMedGoogle Scholar
  46. Luo, Y., Bolon, B., Kahn, S., Bennett, B. D., Babu-Khan, S., Denis, P., et al. (2001). Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nature Neuroscience, 4, 231–232.CrossRefPubMedGoogle Scholar
  47. Maretzky, T., Schulte, M., Ludwig, A., Rose-John, S., Blobel, C., Hartmann, D., et al. (2005). L1 is sequentially processed by two differently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Molecular and Cellular Biology, 25, 9040–9053.CrossRefPubMedGoogle Scholar
  48. Meziane, H., Dodart, J. C., Mathis, C., Little, S., Clemens, J., Paul, S. M., et al. (1998). Memory-enhancing effects of secreted forms of the β-amyloid precursor protein in normal and amnestic mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 12683–12688.CrossRefPubMedGoogle Scholar
  49. Netzer, W. J., Dou, F., Cai, D., Veach, D., Jean, S., Li, Y., et al. (2003). Gleevec inhibits beta-amyloid production but not notch cleavage. Proceedings of the National Academy of Sciences of the United States of America, 100, 12444–12449.CrossRefPubMedGoogle Scholar
  50. Paganetti, P., Calanca, V., Galli, C., Stefani, M., & Molinari, M. (2005). Beta-site specific intrabodies to decrease and prevent generation of Alzheimer's Aβ peptide. Journal of Cell Biology, 168, 863–868.CrossRefPubMedGoogle Scholar
  51. Pangalos, M. N., Jacobsen, S. J., & Reinhart, P. H. (2005). Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the beta-amyloid peptide. Biochemical Society Transactions, 33, 553–558.CrossRefPubMedGoogle Scholar
  52. Parkin, E. T., Hussain, I., Karran, E. H., Turner, A. J., & Hooper, N. M. (1999). Characterisation of detergent-insoluble complexes containing the familial Alzheimer's disease-associated presenilins. Journal of Neurochemistry, 72, 1534–1543.CrossRefPubMedGoogle Scholar
  53. Parkin, E. T., Hussain, I., Turner, A. J., & Hooper, N. M. (1997). The amyloid precursor protein is not enriched in caveolae-like, detergent-insoluble membrane microdomains. Journal of Neurochemistry, 69, 2179–2188.PubMedCrossRefGoogle Scholar
  54. Parkin, E. T., Trew, A., Christie, G., Faller, A., Mayer, R., Turner, A. J., et al. (2002). Structure-activity relationship of hydroxamate-based inhibitors on the secretases that cleave the amyloid precursor protein, angiotensin converting enzyme, CD23, and pro-tumor necrosis factor-alpha. Biochemistry, 41, 4972–4981.CrossRefPubMedGoogle Scholar
  55. Parkin, E. T., Watt, N. T., Hussain, I., Eckman, E. A., Eckman, C. B., Manson, J. C., Baybutt, H. N., Turner, A. J., & Hooper, N. M. (2007). Cellular prior protein regulates β-cleavage of the Alzheimer's amyloid precursor protein. Proceedings of the National Academy of Sciences USA, in press.Google Scholar
  56. Parvathy, S., Karran, E. H., Turner, A. J., & Hooper, N. M. (1998). The secretases that cleave angiotensin converting enzyme and the amyloid precursor protein are distinct from tumour necrosis factor-α convertase. FEBS Letters, 431, 63–65.CrossRefPubMedGoogle Scholar
  57. Petit, A., Bihel, F., da Costa, C. A., Pourquie, O., Checler, F., & Kraus, J. L. (2001). New protease inhibitors prevent gamma-secretase-mediated production of Aβ40/42 without affecting notch cleavage. Nature Cell Biology, 3, 507–511.CrossRefPubMedGoogle Scholar
  58. Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., et al. (2004). A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. The Journal of Clinical Investigation, 113, 1456–1464.PubMedGoogle Scholar
  59. Refolo, L. M., Pappolla, M. A., LaFrancois, J., Malester, B., Schmidt, S. D., Thomas-Bryant, T., et al. (2001). A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiology of Disease, 8, 890–899.CrossRefPubMedGoogle Scholar
  60. Riddell, D. R., Christie, G., Hussain, I., & Dingwall, C. (2001). Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Current Biology, 11, 1288–1293.CrossRefPubMedGoogle Scholar
  61. Savage, M. J., Trusko, S. P., Howland, D. S., Pinsker, L. R., Mistretta, S., Reaume, A. G., et al. (1998). Turnover of amyloid β-protein in mouse brain and acute reduction of its level by phorbol ester. The Journal of Neuroscience, 18, 1743–1752.PubMedGoogle Scholar
  62. Selkoe, D. J. (2001). Alzheimer's disease: Genes, proteins, and therapy. Physiological Reviews, 81, 741–766.PubMedGoogle Scholar
  63. Siemers, E., Skinner, M., Dean, R. A., Gonzales, C., Satterwhite, J., Farlow, M., et al. (2005). Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clinical Neuropharmacology, 28, 126–132.CrossRefPubMedGoogle Scholar
  64. Simons, K., & Ehehalt, R. (2002). Cholesterol, lipid rafts, and disease. The Journal of Clinical Investigation, 110, 597–603.PubMedGoogle Scholar
  65. Singer, O., Marr, R. A., Rockenstein, E., Crews, L., Coufal, N. G., Gage, F. H., et al. (2005). Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nature Neuroscience, 8, 1343–1349.CrossRefPubMedGoogle Scholar
  66. Spoelgen, R., von Arnim, C. A. F., Thomas, A. V., Peltan, I. D., Koker, M., Deng, A., et al. (2006). Interaction of the cytosolic domains of sorLA/lr11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. The Journal of Neuroscience, 26, 418–428.CrossRefPubMedGoogle Scholar
  67. Struhl, G., & Greenwald, I. (1999). Presenilin is required for activity and nuclear access of notch in Drosophila. Nature, 398, 522–525.CrossRefPubMedGoogle Scholar
  68. Van Nostrand, W. E., Wagner, S. L., Shankle, W. D., Farrow, J. S., Dick, M., Rozemuller, J. M., et al. (1992). Decreased levels of soluble amyloid β-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proceedings of the National Academy of Sciences of the United States of America, 89, 2552–2555.CrossRefGoogle Scholar
  69. Vardy, E. R. L. C., Catto, A. J., & Hooper, N. M. (2005). Proteolytic mechanisms in amyloid-beta metabolism: Therapeutic implications for Alzheimer's disease. Trends in Molecular Medicine, 11, 464–472.CrossRefPubMedGoogle Scholar
  70. Vardy, E. R. L. C., Hussain, I., & Hooper, N. M. (2006). Emerging therapeutics for Alzheimer's disease. Expert Review of Neurotherapeutics, 6, 695–704.CrossRefPubMedGoogle Scholar
  71. Wahrle, S., Das, P., Nyborg, A. C., McLendon, C., Shoji, M., Kawarabayashi, T., et al. (2002). Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiology of Disease, 9, 11–23.CrossRefPubMedGoogle Scholar
  72. Wolozin, B. (2001). A fluid connection: Cholesterol and Aβ Proceedings of the National Academy of Sciences of the United States of America, 98, 5371–5373.CrossRefPubMedGoogle Scholar
  73. Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G., & Siegel, G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme a reductase inhibitors. Archives of Neurology, 57, 1439–1443.CrossRefPubMedGoogle Scholar
  74. Wong, H. K., Sakurai, T., Oyama, F., Kaneko, K., Wada, K., Miyazaki, H., et al. (2005). Beta subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. The Journal of Biological Chemistry, 280, 23009–23017.CrossRefPubMedGoogle Scholar
  75. Xie, J., & Guo, Q. (2005). Par-4 is involved in regulation of beta-secretase cleavage of the Alzheimer amyloid precursor protein. The Journal of Biological Chemistry, 280, 13824–13832.CrossRefPubMedGoogle Scholar
  76. Zhang, Z., Nadeau, P., Song, W., Donoviel, D., Yuan, M., Bernstein, A., et al. (2000). Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of notch-1. Nature Cell Biology, 2, 463–465.CrossRefPubMedGoogle Scholar
  77. Zimmermann, M., Gardoni, F., Marcello, E., Colciaghi, F., Borroni, B., Padovani, A., et al. (2004). Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines. Journal of Neurochemistry, 90, 1489–1499.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Nigel M. Hooper
    • 1
  • Emma R. L. C. Vardy
    • 1
  1. 1.Proteolysis Research GroupUniversity of LeedsUK

Personalised recommendations