Delta Secretase and BDNF Signalling in Alzheimer’s Disease

Abstract

As one of the major contributors of the central nervous system, neurons require neurotrophic factors, which are synthesized from neighbouring cells, for several cellular processes, such as neuronal survival, growth, and differentiation. Neurotrophic factors are categorized into the neurotrophin family, the neuropoietic cytokines, and the glial cell-derived neurotrophic factor. The neurotrophin family comprises four growth factors: nerve growth factor (NGF), neurotrophin-3 (NT3), neurotrophin-4 (NT4), and brain-derived neurotrophic factor (BDNF). One of the best-known neurotrophic factors is BDNF. Its importance is based on its central role in neuronal survival. Entry of the BDNF into the neurons occurs via TrkB receptors, and it is transported to the cell body along microtubules in axons. As it is known in the brains of Alzheimer's patients, the axonal transport of BDNF is destructed via the hyperphosphorylated tau. There are several causes for the hyperphosphorylation of tau. Among them, delta secretase (δ-secretase), a lysosomal cysteine protease, cleaves both amyloid precursor protein (APP) and tau. It is supposed to play an essential role in tau hyperphosphorylation, particularly in the aging brain. In this review, we focus on the activity of δ-secretase, how it leads to tau hyperphosphorylation, and how it disrupts the axonal transport of BDNF in Alzheimer's disease

Keywords

• BDNF
• axonal transport
• delta secretase
• Alzheimer’s disease
• APP
• tau protein

References

1. 1. Association As. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12(4): 459-509. [CrossRef] google scholar
2. 2. Kumar A, Sidhu J, Goyal A, Tsao JW, Doerr C. Alzheimer Disease (Nursing). StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.; 2022. google scholar
3. 3. Ovsepian SV, O’Leary VB, Zaborszky L, Ntziachristos V, Dolly JO. Amyloid plaques of Alzheimer’s Disease as hotspots of glutamatergic activity. Neuroscientist 2019; 25(4): 288-97. [CrossRef] google scholar
4. 4. Kuznetsov IA, Kuznetsov AV. How the formation of amyloid plaques and neurofibrillary tangles may be related: a mathematical modelling study. Proc Math Phys Eng Sci 2018; 474(2210): 20170777. [CrossRef] google scholar
5. 5. Zhang Z, Song M, Liu X, Su Kang S, Duong DM, Seyfried NT, et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat Commun 2015; 6: 8762. [CrossRef] google scholar
6. 6. Rodríguez-Martín T, Cuchillo-Ibáñez I, Noble W, Nyenya F, Anderton BH, Hanger DP. Tau phosphorylation affects its axonal transport and degradation. Neurobiol Aging 2013; 34(9): 2146-57. [CrossRef] google scholar
7. 7. Ashrafian H, Zadeh EH, Khan RH. Review on Alzheimer’s disease: Inhibition of amyloid beta and tau tangle formation. Int J Biol Macromol 2021; 167: 382-94. [CrossRef] google scholar
8. 8. Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med 2014; 20(11): 1254-62. [CrossRef] google scholar

9. 9. Xiang J, Wang ZH, Ahn EH, Liu X, Yu SP, Manfredsson FP, et al. Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies. Proc Natl Acad Sci U S A 2019; 116(18): 9094-102. [CrossRef] google scholar
10. 10. Chen SD, Wu CL, Hwang WC, Yang DI. More Insight into BDNF against neurodegeneration: Anti-apoptosis, anti-Oxidation, and suppression of autophagy. Int J Mol Sci 2017; 18(3): 545 [CrossRef] google scholar
11. 11. Miranda-Lourenço C, Ribeiro-Rodrigues L, Fonseca-Gomes J, Tanqueiro SR, Belo RF, Ferreira CB, et al. Challenges of BDNF-based therapies: From common to rare diseases. Pharmacol Res 2020; 162: 105281. [CrossRef] google scholar
12. 12. Boyd JG, Gordon T. Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Mol Neurobiol 2003; 27(3): 277-324. [CrossRef] google scholar
13. 13. Huang EJ, Reichardt LF. Trk receptors: Roles in neuronal signal transduction. Annu Rev Biochem 2003; 72: 609-42. [CrossRef] google scholar
14. 14. Teng KK, Felice S, Kim T, Hempstead BL. Understanding proneurotrophin actions: Recent advances and challenges. Dev Neurobiol 2010; 70(5): 350-9. [CrossRef] google scholar
15. 15. Yamada K, Nabeshima T. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 2003; 91(4): 26770. [CrossRef] google scholar
16. 16. Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 2009; 5(6): 311-22. [CrossRef] google scholar
17. 17. Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T. Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 2007; 85(3): 525-35. [CrossRef] google scholar
18. 18. Lessmann V, Brigadski T. Mechanisms, locations, and kinetics of synaptic BDNF secretion: An update. Neurosci Res 2009; 65(1): 1122. [CrossRef] google scholar
19. 19. Kowianski P, Lietzau G, Czuba E, Waskow M, Steliga A, Morys J. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol 2018; 38(3): 579-93. [CrossRef] google scholar
20. 20. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for longterm hippocampal plasticity. Science 2004; 306(5695): 487-91. [CrossRef] google scholar
21. 21. Ghosh A, Carnahan J, Greenberg ME. Requirement for BDNF in activity-dependent survival of cortical neurons. Science 1994; 263(5153): 1618-23. [CrossRef] google scholar
22. 22. Malik SC, Sozmen EG, Baeza-Raja B, Le Moan N, Akassoglou K, Schachtrup C. In vivo functions of p75(NTR): challenges and opportunities for an emerging therapeutic target. Trends Pharmacol Sci 2021; 42(9): 772-88. [CrossRef] google scholar
23. 23. Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 2002; 67(3): 203-33. [CrossRef] google scholar
24. 24. Lee-Hotta S, Uchiyama Y, Kametaka S. Role of the BDNF-TrkB pathway in KCC2 regulation and rehabilitation following neuronal injury: A mini review. Neurochem Int 2019; 128: 32-8. [CrossRef] google scholar
25. 25. Yoshii A, Constantine-Paton M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 2010; 70(5): 304-22. [CrossRef] google scholar
26. 26. Guo W, Nagappan G, Lu B. Differential effects of transient and sustained activation of BDNF-TrkB signaling. Dev Neurobiol 2018; 78(7): 647-59. [CrossRef] google scholar
27. 27. Zhang Z, Tian Y, Ye K. ô-secretase in neurodegenerative diseases: Mechanisms, regulators and therapeutic opportunities. Transl Neurodegener 2020; 9: 1. [CrossRef] google scholar
28. 28. Dall E, Brandstetter H. Structure and function of legumain in health and disease. Biochimie 2016; 122: 126-50. [CrossRef] google scholar
29. 29. Liu C, Sun C, Huang H, Janda K, Edgington T. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003; 63(11): 2957-64. google scholar
30. 30. Wang ZH, Liu P, Liu X, Manfredsson FP, Sandoval IM, Yu SP, et al. Delta-secretase phosphorylation by srpk2 enhances its enzymatic activity, provoking pathogenesis in Alzheimer’s Disease. Mol Cell 2017; 67(5): 812-25.e5. [CrossRef] google scholar
31. 31. Xia Y, Wang ZH, Zhang Z, Liu X, Yu SP, Wang JZ, et al. Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer’s disease. Prog Neurobiol 2021; 204: 102113. [CrossRef] google scholar
32. 32. Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 2009; 15(3): 112-9. [CrossRef] google scholar
33. 33. Kang SS, Ahn EH, Ye K. Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer’s disease. Exp Mol Med 2020; 52(8): 1275-87. [CrossRef] google scholar
34. 34. Liao J, Chen C, Ahn EH, Liu X, Li H, Edgington-Mitchell LE, et al. Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer’s disease. Neuropharmacology 2021; 197: 108737. [CrossRef] google scholar
35. 35. Wang ZH, Wu W, Kang SS, Liu X, Wu Z, Peng J, et al. BDNF inhibits neurodegenerative disease-associated asparaginyl endopeptidase activity via phosphorylation by AKT. JCI Insight 2018; 3(16): e99007 [CrossRef] google scholar
36. 36. Huuha AM, Norevik CS, Moreira JBN, Kobro-Flatmoen A, Scrimgeour N, Kivipelto M, et al. Can exercise training teach us how to treat Alzheimer’s disease? Ageing Res Rev 2022; 75: 101559. [CrossRef] google scholar
37. 37. Wang ZH, Gong K, Liu X, Zhang Z, Sun X, Wei ZZ, et al. C/EBPß regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nat Commun 2018; 9(1): 1784. [CrossRef] google scholar
38. 38. Xia Y, Wang ZH, Liu P, Edgington-Mitchell L, Liu X, Wang XC, et al. TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer’s disease pathologies. Mol Psychiatry 2021; 26(7): 2943-63. [CrossRef] google scholar
39. 39. Basurto-Islas G, Grundke-Iqbal I, Tung YC, Liu F, Iqbal K. Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease. J Biol Chem 2013; 288(24): 17495-507. [CrossRef] google scholar
40. 40. Basurto-Islas G, Gu JH, Tung YC, Liu F, Iqbal K. Mechanism of tau hyperphosphorylation involving lysosomal enzyme asparagine endopeptidase in a mouse model of brain ischemia. J Alzheimers Dis 2018; 63(2): 821-33. [CrossRef] google scholar
41. 41. Madeira A, Pommet JM, Prochiantz A, Allinquant B. SET protein (TAF1beta, I2PP2A) is involved in neuronal apoptosis induced by an amyloid precursor protein cytoplasmic subdomain. Faseb J 2005; 19(13): 1905-7. [CrossRef] google scholar
42. 42. Liu GP, Wei W, Zhou X, Zhang Y, Shi HH, Yin J, et al. I(2)(PP2A) regulates p53 and Akt correlatively and leads the neurons to abort apoptosis. Neurobiol Aging 2012; 33(2): 254-64. [CrossRef] google scholar
43. 43. Sleigh JN, Rossor AM, Fellows AD, Tosolini AP, Schiavo G. Axonal transport and neurological disease. Nat Rev Neurol 2019; 15(12): 691-703. [CrossRef] google scholar
44. 44. Terenzio M, Schiavo G, Fainzilber M. Compartmentalized signaling in neurons: from cell biology to neuroscience. Neuron 2017; 96(3): 667-79. [CrossRef] google scholar
45. 45. Ye X, Tai W, Zhang D. The early events of Alzheimer’s disease pathology: From mitochondrial dysfunction to BDNF axonal transport deficits. Neurobiol Aging 2012; 33(6): 1122.e1-10. [CrossRef] google scholar
46. 46. Brandt R, Léger J, Lee G. Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J Cell Biol 1995; 131(5): 1327-40. [CrossRef] google scholar
47. 47. Cuchillo-Ibanez I, Seereeram A, Byers HL, Leung KY, Ward MA, Anderton BH, et al. Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin. Faseb J 2008; 22(9): 3186-95. [CrossRef] google scholar
48. 48. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, et al. Tau reduction prevents Aß-induced defects in axonal transport. Science 2010; 330(6001): 198. [CrossRef] google scholar
49. 49. Segal RA. Selectivity in neurotrophin signaling: Theme and variations. Annu Rev Neurosci 2003; 26: 299-330. [CrossRef] google scholar
50. 50. Poon WW, Blurton-Jones M, Tu CH, Feinberg LM, Chabrier MA, Harris JW, et al. ß-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiol Aging 2011; 32(5): 821-33. [CrossRef] google scholar