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Powering Amyloid Beta Degrading Enzymes: A Possible Therapy for Alzheimer’s Disease

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Abstract

The accumulation of amyloid beta (Aβ) in the brain is believed to play a central role in the development and progression of Alzheimer’s disease. Revisions to the amyloid cascade hypothesis now acknowledge the dynamic equilibrium in which Aβ exists and the importance of enzymes involved in the production and breakdown of Aβ in maintaining healthy Aβ levels. However, while a wealth of pharmacological and immunological therapies are being generated to inhibit the Aβ-producing enzymes, β-site APP cleavage enzyme 1 and γ-secretase, the therapeutic potential of stimulating Aβ-degrading enzymes such as neprilysin, endothelin-converting enzyme-1 and insulin-degrading enzyme remains relatively unexplored. Recent evidence indicates that increasing Aβ degradation as opposed to inhibiting synthesis is a more effective strategy to prevent Aβ build-up. Therefore Aβ degrading enzymes have become valuable targets of therapy. In this review, we discuss the pathway of Aβ synthesis and clearance along with the opportunities they present for therapeutic intervention, the benefits of increasing the expression/activity of Aβ-degrading enzymes, and the untapped therapeutic potential of enzyme activation.

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References

  1. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30:11938–11950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shankar GM, Walsh DM (2009) Alzheimer’s disease: synaptic dysfunction and Abeta. Mol Neurodegener 4:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tsai J, Grutzendler J, Duff K, Gan WB (2004) Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181–1183

    Article  CAS  PubMed  Google Scholar 

  5. Muller U, Winter P, Graeber MB (2013) A presenilin 1 mutation in the first case of Alzheimer’s disease. Lancet Neurol 12:129–130

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  9. Nalivaeva NN, Belyaev ND, Zhuravin IA, Turner AJ (2012) The Alzheimer’s amyloid-degrading peptidase, neprilysin: can we control it? Int J Alzheimers Dis 2012:383796

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chow VW, Mattson MP, Wong PC, Gleichmann M (2010) An overview of APP processing enzymes and products. Neuromol Med 12:1–12

    Article  CAS  Google Scholar 

  12. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2:a006270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, Arancio O (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28:14537–14545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baruch-Suchodolsky R, Fischer B (2009) Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems. Biochemistry 48:4354–4370

    Article  CAS  PubMed  Google Scholar 

  15. Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S, Danni O, Parola M, Smith MA, Perry G, Tamagno E, Tabaton M (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem 108:1045–1056

    Article  CAS  PubMed  Google Scholar 

  16. Igbavboa U, Sun GY, Weisman GA, He Y, Wood WG (2009) Amyloid beta-protein stimulates trafficking of cholesterol and caveolin-1 from the plasma membrane to the Golgi complex in mouse primary astrocytes. Neuroscience 162:328–338

    Article  CAS  PubMed  Google Scholar 

  17. Yao ZX, Papadopoulos V (2002) Function of beta-amyloid in cholesterol transport: a lead to neurotoxicity. FASEB J 16:1677–1679

    Article  CAS  PubMed  Google Scholar 

  18. Bailey JA, Maloney B, Ge YW, Lahiri DK (2011) Functional activity of the novel Alzheimer’s amyloid beta-peptide interacting domain (AbetaID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis. Gene 488:13–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Maloney B, Lahiri DK (2011) The Alzheimer’s amyloid beta-peptide (Abeta) binds a specific DNA Abeta-interacting domain (AbetaID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motif. Gene 488:1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ (2012) Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease? J Neurochem 120(Suppl 1):167–185

    Article  CAS  PubMed  Google Scholar 

  21. Bates KA, Verdile G, Li QX, Ames D, Hudson P, Masters CL, Martins RN (2009) Clearance mechanisms of Alzheimer’s amyloid-beta peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry 14:469–486

    Article  CAS  PubMed  Google Scholar 

  22. Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, Xu F, Parisi M, LaRue B, Hu HW, Spijkers P, Guo H, Song X, Lenting PJ, Van Nostrand WE, Zlokovic BV (2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43:333–344

    Article  CAS  PubMed  Google Scholar 

  23. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Investig 106:1489–1499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, Heise CE, Hoyte K, Luk W, Lu Y, Peng K, Wu P, Rouge L, Zhang Y, Lazarus RA, Scearce-Levie K, Wang W, Wu Y, Tessier-Lavigne M, Watts RJ (2011) A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci Transl Med 3:84ra43

    Article  CAS  PubMed  Google Scholar 

  25. Yan R (2016) Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs. Transl Neurodegener 5:13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS, Alzheimer’s Disease Cooperative Study Steering C, Siemers E, Sethuraman G, Mohs R, Semagacestat Study G (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369:341–350

    Article  CAS  PubMed  Google Scholar 

  27. Vlad SC, Miller DR, Kowall NW, Felson DT (2008) Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70:1672–1677

    Article  CAS  PubMed  Google Scholar 

  28. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Investig 112:440–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH, Tarenflurbil Phase 3 Study G (2009) Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302:2557–2564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Szekely CA, Green RC, Breitner JC, Ostbye T, Beiser AS, Corrada MM, Dodge HH, Ganguli M, Kawas CH, Kuller LH, Psaty BM, Resnick SM, Wolf PA, Zonderman AB, Welsh-Bohmer KA, Zandi PP (2008) No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. Neurology 70:2291–2298

    Article  CAS  PubMed  Google Scholar 

  31. Garcia-Alloza M, Subramanian M, Thyssen D, Borrelli LA, Fauq A, Das P, Golde TE, Hyman BT, Bacskai BJ (2009) Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575. Mol Neurodegener 4:19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46–54

    Article  CAS  PubMed  Google Scholar 

  33. Eckman EA, Reed DK, Eckman CB (2001) Degradation of the Alzheimer’s amyloid beta peptide by endothelin-converting enzyme. J Biol Chem 276:24540–24548

    Article  CAS  PubMed  Google Scholar 

  34. Pacheco-Quinto J, Herdt A, Eckman CB, Eckman EA (2013) Endothelin-converting enzymes and related metalloproteases in Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S101–S110

    PubMed  PubMed Central  Google Scholar 

  35. Nalivaeva NN, Turner AJ (2017) Role of ageing and oxidative stress in regulation of Amyloid-degrading enzymes and development of neurodegeneration. Curr Aging Sci 10:32–40

    Article  CAS  PubMed  Google Scholar 

  36. Turner AJ, Nalivaeva NN (2013) Peptide degradation (Neprilysin and other regulatory peptidases). In: Kastin AJ (ed) Handbook of biologically active peptides. Elsevier, San Diego, pp 1757–1764

    Chapter  Google Scholar 

  37. Miners JS, Barua N, Kehoe PG, Gill S, Love S (2011) Abeta-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol 70:944–959

    Article  CAS  PubMed  Google Scholar 

  38. Saido T, Leissring MA (2012) Proteolytic degradation of amyloid beta-protein. Cold Spring Harb Perspect Med 2:a006379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dolev I, Michaelson DM (2004) A nontransgenic mouse model shows inducible amyloid-beta (Abeta) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade. Proc Natl Acad Sci USA 101:13909–13914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nisemblat Y, Belinson H, Dolev I, Michaelson DM (2008) Activation of the amyloid cascade by intracerebroventricular injection of the protease inhibitor phosphoramidon. Neuro-degener Dis 5:166–169

    Article  CAS  Google Scholar 

  41. Marr RA, Rockenstein E, Mukherjee A, Kindy MS, Hersh LB, Gage FH, Verma IM, Masliah E (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 23:1992–1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Marr RA, Spencer BJ (2010) NEP-like endopeptidases and Alzheimer’s disease. Curr Alzheimer Res 7:223–229

    Article  CAS  PubMed  Google Scholar 

  43. Hafez D, Huang JY, Huynh AM, Valtierra S, Rockenstein E, Bruno AM, Lu B, DesGroseillers L, Masliah E, Marr RA (2011) Neprilysin-2 is an important beta-amyloid degrading enzyme. Am J Pathol 178:306–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Eckman EA, Watson M, Marlow L, Sambamurti K, Eckman CB (2003) Alzheimer’s disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. J Biol Chem 278:2081–2084

    Article  CAS  PubMed  Google Scholar 

  45. Kilger E, Buehler A, Woelfing H, Kumar S, Kaeser SA, Nagarathinam A, Walter J, Jucker M, Coomaraswamy J (2011) BRI2 protein regulates beta-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE). J Biol Chem 286:37446–37457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 100:4162–4167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bernstein KE, Koronyo Y, Salumbides BC, Sheyn J, Pelissier L, Lopes DH, Shah KH, Bernstein EA, Fuchs DT, Yu JJ, Pham M, Black KL, Shen XZ, Fuchs S, Koronyo-Hamaoui M (2014) Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline. J Clin Investig 124:1000–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu FF, Turk J, Xu J, Hsu CY, Mills JC, Holtzman DM, Lee JM (2006) Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 26:10939–10948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu RM, van Groen T, Katre A, Cao D, Kadisha I, Ballinger C, Wang L, Carroll SL, Li L (2011) Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer’s disease. Neurobiol Aging 32:1079–1089

    Article  CAS  PubMed  Google Scholar 

  50. Jacobsen JS, Comery TA, Martone RL, Elokdah H, Crandall DL, Oganesian A, Aschmies S, Kirksey Y, Gonzales C, Xu J, Zhou H, Atchison K, Wagner E, Zaleska MM, Das I, Arias RL, Bard J, Riddell D, Gardell SJ, Abou-Gharbia M, Robichaud A, Magolda R, Vlasuk GP, Bjornsson T, Reinhart PH, Pangalos MN (2008) Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci USA 105:8754–8759

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen J, Wang X, Yu G, Esposito L, Mucke L, Gan L (2006) Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease. Neuron 51:703–714

    Article  CAS  PubMed  Google Scholar 

  52. Yamin R, Zhao C, O’Connor PB, McKee AC, Abraham CR (2009) Acyl peptide hydrolase degrades monomeric and oligomeric amyloid-beta peptide. Mol Neurodegener 4:33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hemming ML, Patterson M, Reske-Nielsen C, Lin L, Isacson O, Selkoe DJ (2007) Reducing amyloid plaque burden via ex vivo gene delivery of an Abeta-degrading protease: a novel therapeutic approach to Alzheimer disease. PLoS Med 4:e262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jin X, Yang YD, Li YM (2008) Gene therapy: regulations, ethics and its practicalities in liver disease. World J Gastroenterol 14:2303–2307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cabrol C, Huzarska MA, Dinolfo C, Rodriguez MC, Reinstatler L, Ni J, Yeh LA, Cuny GD, Stein RL, Selkoe DJ, Leissring MA (2009) Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening. PLoS ONE 4:e5274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ayoub S, Melzig MF (2006) Induction of neutral endopeptidase (NEP) activity of SK-N-SH cells by natural compounds from green tea. J Pharm Pharmacol 58:495–501

    Article  CAS  PubMed  Google Scholar 

  57. Niikura T, Sidahmed E, Hirata-Fukae C, Aisen PS, Matsuoka Y (2011) A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice. PLoS ONE 6:e16259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Klein C, Patte-Mensah C, Taleb O, Bourguignon JJ, Schmitt M, Bihel F, Maitre M, Mensah-Nyagan AG (2013) The neuroprotector kynurenic acid increases neuronal cell survival through neprilysin induction. Neuropharmacology 70:254–260

    Article  CAS  PubMed  Google Scholar 

  59. Smith AI, Rajapakse NW, Kleifeld O, Lomonte B, Sikanyika NL, Spicer AJ, Hodgson WC, Conroy PJ, Small DH, Kaye DM (2016) N-terminal domain of Bothrops asper myotoxin II enhances the activity of endothelin converting enzyme-1 and neprilysin. Sci Rep 6:22413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Camargo AC, Ianzer D, Guerreiro JR, Serrano SM (2012) Bradykinin-potentiating peptides: beyond captopril. Toxicon 59:516–523

    Article  CAS  PubMed  Google Scholar 

  61. Furman BL (2012) The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. Toxicon 59:464–471

    Article  CAS  PubMed  Google Scholar 

  62. Hamad MK, He K, Abdulrazeq HF, Mustafa AM, Luceri R, Kamal N, Ali M, Nakhla J, Herzallah MM, Mammis A (2018) Potential uses of isolated toxin peptides in neuropathic pain relief: a literature review. World Neurosurg 113:333–347 e335

    Article  PubMed  Google Scholar 

  63. Dannhardt G, Kiefer W (2001) Cyclooxygenase inhibitors–current status and future prospects. Eur J Med Chem 36:109–126

    Article  CAS  PubMed  Google Scholar 

  64. McFarlane SI, Kumar A, Sowers JR (2003) Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol 91:30H–37H

    Article  CAS  PubMed  Google Scholar 

  65. Sweitzer NK (2003) What is an angiotensin converting enzyme inhibitor? Circulation 108:e16–e18

    Article  PubMed  Google Scholar 

  66. Istvan ES, Deisenhofer J (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292:1160–1164

    Article  CAS  PubMed  Google Scholar 

  67. van Spronsen FJ (2010) Phenylketonuria: a 21st century perspective. Nat Rev Endocrinol 6:509–514

    Article  CAS  PubMed  Google Scholar 

  68. Mehta D, Jackson R, Paul G, Shi J, Sabbagh M (2017) Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert Opin Investig Drugs 26:735–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Dore V, Fowler C, Li QX, Martins R, Rowe C, Tomita T, Matsuzaki K, Ishii K, Ishii K, Arahata Y, Iwamoto S, Ito K, Tanaka K, Masters CL, Yanagisawa K (2018) High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 554:249–254

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Virginia Wilke and John Farrell Postgraduate Research Scholarship, the Yulgilbar Alzheimer’s Research Program and Monash University.

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  1. Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia

    Nkumbu L. Sikanyika, Helena C. Parkington, A. Ian Smith & Sanjaya Kuruppu

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  1. Nkumbu L. Sikanyika
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Sikanyika, N.L., Parkington, H.C., Smith, A.I. et al. Powering Amyloid Beta Degrading Enzymes: A Possible Therapy for Alzheimer’s Disease. Neurochem Res 44, 1289–1296 (2019). https://doi.org/10.1007/s11064-019-02756-x

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