Inhibition and modulation of γ-secretase for Alzheimer’s disease

Summary

The 4-kDa amyloid β-peptide (Aβ) is strongly implicated the pathogenesis of Alzheimer’s disease (AD), and this peptide is cut out of the amyloid β-protein precursor (APP) by the sequential action of β- and γ-secretases. γ-Secretase is a membrane-embedded protease complex that cleaves the transmembrane region of APP to produce Aβ, and this protease is a top target for developing AD therapeutics. A number of inhibitors of the γ-secretase complex have been identified, including peptidomimetics that block the active site, helical peptides that interact with the initial substrate docking site, and other less peptide-like, more drug-like compounds. To date, one γ-secretase inhibitor has advanced into late-phase clinical trials for the treatment of AD, but serious concerns remain. The γ-secretase complex cleaves a number of other substrates, and γ-secretase inhibitors cause in vivo toxicities by blocking proteolysis of one essential substrate, the Notch receptor. Thus, compounds that modulate γ-secretase, rather than inhibit it, to selectively alter Aβ production without hindering signal transduction from the Notch receptor would be more ideal. Such modulators have been discovered and advanced, with one compound in late-phase clinical trials, renewing interest in γ-secretase as a therapeutic target.

References

  1. 1.

    Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M. Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau [Erratum in: Nat Neurosci 1998;1:743]. Nat Neurosci 1998;1: 355–358.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001;24: 1121–1159.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81: 741–766.

    CAS  PubMed  Google Scholar 

  4. 4.

    Jarrett JT, Berger EP, Lansbury PT Jr. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 1993;32: 4693–4697.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 1994;13: 45–53.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297: 353–356.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375: 754–760.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995; 269: 973–977.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 1995;376: 775–778.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996;2: 864–870.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Duff K, Eckman C, Zehr C, et al. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 1996;383: 710–713.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Lemere CA, Lopera F, Kosik KS, et al. The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology. Nat Med 1996;2: 1146–1150.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Citron M, Westaway D, Xia W, et al. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 1997; 3: 67–72.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Thinakaran G, Borchelt DR, Lee MK, et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996;17: 181–190.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Ratovitski T, Slunt HH, Thinakaran G, Rice DL, Sisodia SS, Borchelt DR. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem 1997;272: 24536–24541.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Capell A, Grunberg J, Pesold B, et al. The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100-50-kDa molecular mass complex. J Biol Chem 1998;273: 3205–3211.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998;391: 387–390.

    Article  PubMed  Google Scholar 

  18. 18.

    Herreman A, Semeels L, Annaert W, Collen D, Schoonjans L, De Strooper B. Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2000;2: 461–462.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Zhang Z, Nadeau P, Song W, et al. Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2000;2: 463–465.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Wolfe MS, Xia W, Moore CL, et al. Peptidomimetic probes and molecular modeling suggest Alzheimer’s γ-secretases are intramembrane-cleaving aspartyl proteases. Biochemistry 1999;38: 4720–4727.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 1999;398: 513–517.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Wolfe MS, De Los Angeles J, Miller DD, Xia W, Selkoe DJ. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer’s disease. Biochemistry 1999;38: 11223–11230.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Li YM, Xu M, Lai MT, et al. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000;405: 689–694.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Esler WP, Kimberly WT, Ostaszewski BL, et al. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat Cell Biol 2000;2: 428–434.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Esler WP, Kimberly WT, Ostaszewski BL, et al. Activity-dependent isolation of the presenilin/γ-secretase complex reveals nicastrin and a γ substrate. Proc Natl Acad Sci U S A 2002;99: 2720–2725.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 2003;100: 6382–6387.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Yu G, Nishimura M, Arawaka S, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 2000;407: 48–54.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Goutte C, Tsunozaki M, Hale VA, Priess JR. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 2002; 99: 775–779.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Francis R, McGrath G, Zhang J, et al. Aph-1 and Pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev Cell 2002;3: 85–97.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the γ-secretase complex. Nature 2003;422: 438–441.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of γ-secretase activity. Nat Cell Biol 2003;5: 486–488.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Fraering PC, Ye W, Strub JM, et al. Purification and characterization of the human γ-secretase complex. Biochemistry 2004;43: 9774–9789.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Shah S, Lee SF, Tabuchi K, et al. Nicastrin functions as a γ-secretase-substrate receptor. Cell 2005;122: 435–447.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Zhou S, Zhou H, Walian PJ, Jap BK. CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer’ s disease amyloid β-peptide production. Proc Natl Acad Sci U S A 2005;102: 7499–7504.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 2002;296: 2215–2218.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    LaVoie MJ, Fraering PC, Ostaszewski BL, et al. Assembly of the γ-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin. J Biol Chem 2003;278: 37213–37222.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Morais VA, Crystal AS, Pijak DS, et al. The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the γ-secretase complex. J Biol Chem 2003;278: 43284–43291.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Shirotani K, Edbauer D, Kostka M, Steiner H, Haass C. Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1. J Neurochem 2004;89: 1520–1527.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Hu Y, Fortini ME. Different cofactor activities in γ-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex. J Cell Biol 2003;161: 685–690.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Fraering PC, LaVoie MJ, Ye W, et al. Detergent-dependent dissociation of active γ-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. Biochemistry 2004;43: 323–333.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T. Pen-2 is incorporated into the γ-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 2005;280: 41967–41975.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Kim SH, Sisodia SS. Evidence that the “NF” motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. J Biol Chem 2005;280: 41953–41966.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Das C, Berezovska O, Diehl TS, et al. Designed helical peptides inhibit an intramembrane protease. J Am Chem Soc 2003;125: 11794–11795.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Bihel F, Das C, Bowman MJ, Wolfe MS. Discovery of a subnanomolar helical d-tridecapeptide inhibitor of γ-secretase. J Med Chem 2004;47: 3931–3933.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Kornilova AY, Das C, Wolfe MS. Differential effects of inhibitors on the γ-secretase complex: mechanistic implications. J Biol Chem 2003;278: 16470–16473.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Kornilova AY, Bihel F, Das C, Wolfe MS. The initial substrate-binding site of γ-secretase is located on presenilin near the active site. Proc Natl Acad Sci U S A 2005;102: 3230–3235.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Selkoe DJ, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 2003;26: 565–597.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998;393: 382–386.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 1999;398: 518–522.

    Article  PubMed  Google Scholar 

  50. 50.

    Wong PC, Zheng H, Chen H, et al. Presenilin 1 is required for Notchl and DII1 expression in the paraxial mesoderm. Nature 1997;387: 288–292.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in presenilin-1-deficient mice. Cell 1997; 89: 629–639.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Dovey HF, John V, Anderson JP, et al. Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain. J Neurochem 2001;76: 173–181.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Lanz TA, Himes CS, Pallante G, et al. The γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 2003;305: 864–871.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Barten DM, Guss VL, Corsa JA, et al. Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J Pharmacol Exp Ther 2005;312: 635–643.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Anderson JJ, Holtz G, Baskin PP, et al. Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897. Biochem Pharmacol 2005;69: 689–698.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Best JD, Jay MT, Otu F, et al. Quantitative measurement of changes in amyloid-β(40) in the rat brain and cerebrospinal fluid following treatment with the γ-secretase inhibitor LY-411575 [N2-[(2S)2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-Nl-[(7S)5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide]. J Pharmacol Exp Ther 2005;313: 902–908.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Siemers E, Skinner M, Dean RA, et al. Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28: 126–132.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Siemers ER, Quinn JF, Kaye J, et al. Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006;66: 602–604.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin Neuropharmacol 2007;30: 317–325.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Searfoss GH, Jordan WH, Calligaro DO, et al. Adipsin: a biomarker of gastrointestinal toxicity mediated by a functional γ secretase inhibitor. J Biol Chem 2003;278: 46107–46116.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the y-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004;279: 12876–12882.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 2001;414: 212–216.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Weggen S, Eriksen JL, Sagi SA, et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β42 production by direct modulation of γ-secretase activity. J Biol Chem 2003;278: 31831–31837.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Beher D, Clarke EE, Wrigley JD, et al. Selected non-steroidal anti-inflammatory drugs and their derivatives target γ-secretase at a novel site: evidence for an allosteric mechanism. J Biol Chem 2004;279: 43419–43426.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Okochi M, Fukumori A, Jiang J, et al. Secretion of the Notch-1 Aβ-like peptide during Notch signaling. J Biol Chem 2006;281: 7890–7898.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ 42 in vivo. J Clin Invest 2003;112: 440–449.

    CAS  PubMed  Google Scholar 

  67. 67.

    Kukar T, Prescott S, Eriksen JL, et al. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci 2007;8: 54.

    Article  PubMed  Google Scholar 

  68. 68.

    Galasko DR, Graff-Radford N, May S, et al. Safety, tolerability, pharmacokinetics, and Aβ levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord 2007;21: 292–299.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Imbimbo BP, Del Giudice E, Colavito D, et al. l-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel γ-secretase modulator, reduces brain β-amyloid pathology in a transgenic mouse model of Alzheimer’s disease without causing peripheral toxicity. J Pharmacol Exp Ther 2007;323: 822–830.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Jantzen PT, Connor KE, DiCarlo G, et al. Microglial activation and β-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci 2002;22: 2246–2254.

    CAS  PubMed  Google Scholar 

  71. 71.

    Netzer WJ, Dou F, Cai D, et al. Gleevec inhibits β-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A 2003; 100: 12444–12449.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. γ-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide binding site. J Biol Chem 2005;280: 41987–41996.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Kopan R, Ilagan MX. γ-Secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 2004;5: 499–504.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Michael S. Wolfe.

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Wolfe, M.S. Inhibition and modulation of γ-secretase for Alzheimer’s disease. Neurotherapeutics 5, 391–398 (2008). https://doi.org/10.1016/j.nurt.2008.05.010

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Key Words

  • Alzheimer’s disease
  • amyloid β-protein
  • amyloid precursor protein
  • Notch receptor
  • secretase
  • γ-secretase