Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Cathepsin B-A Neuronal Death Mediator in Alzheimer’s Disease Leading to Neurodegeneration

Author(s): Anjali Sharma, Rayala Swetha, Nilesh Gajanan Bajad, Ankit Ganeshpurkar, Ravi Singh, Ashok Kumar and Sushil Kumar Singh*

Volume 22, Issue 15, 2022

Published on: 21 April, 2022

Page: [2012 - 2023] Pages: 12

DOI: 10.2174/1389557522666220214095859

Price: $65

Abstract

The lysosomal cysteine protease enzyme, named Cathepsin B, mainly degrades the protein and manages its average turnover in our body. The Cathepsin B active form is mostly present inside the lysosomal part at a cellular level, providing the slightly acidic medium for its activation. Multiple findings on Cathepsin B reveal its involvement in neurons’ degeneration and a possible role as a neuronal death mediator in several neurodegenerative diseases. In this review article, we highlight the participation of Cathepsin B in the etiology/progress of AD, along with various other factors. The enzyme is involved in producing neurotoxic Aβ amyloid in the AD brain by acting as the β-secretase enzyme in the regulated secretory pathways responsible for APP processing. Aβ amyloid accumulation and amyloid plaque formation lead to neuronal degeneration, one of the prominent pathological hallmarks of AD. Cathepsin B is also involved in the production of PGlu-Aβ, which is a truncated and highly neurotoxic form of Aβ. Some of the findings also revealed that Cathepsin B specific gene deletion decreases the level of PGlu-Aβ inside the brain of experimental mice. Therefore, neurotoxicity might be considered a new pathological indication of AD due to the involvement of Cathepsin B. It also damages neurons present in the CNS region by producing inflammatory responses and generating mitochondrial ROS. However, Cathepsin B inhibitors, i.e., CA-074, can prevent neuronal death in AD patients. The other natural inhibitors are also equally effective against neuronal damage with higher selectivity. Its synthetic inhibitors are specific for their target; however, they lose their selectivity in the presence of quite a few reducing agents. Therefore, a humanized monoclonal antibody is used as a selective Cathepsin B inhibitor to overcome the problem experienced. The use of Cathepsin B for the treatment of AD and other neurodegenerative diseases could be considered a rational therapeutic target.

Keywords: Cathepsin B, β-amyloid, pyroglutamate amyloid- β (PGlu-Aβ), neuroinflammation, regulated secretory pathway, humanized antibody, Alzheimer’s disease.

« Previous Next »
Graphical Abstract

[1]
Rossi, A.; Deveraux, Q.; Turk, B.; Sali, A. Comprehensive search for cysteine cathepsins in the human genome. Biol. Chem., 2004, 385(5), 363-372.
[http://dx.doi.org/10.1515/BC.2004.040] [PMID: 15195995]
[2]
Hong, X.Q.; He, X.Y.; Tam, K.Y.; Chen, W.H. Synthesis and biological effect of lysosome-targeting fluorescent anion transporters with enhanced anionophoric activity. Bioorg. Med. Chem. Lett., 2020, 30(19), 127461.
[http://dx.doi.org/10.1016/j.bmcl.2020.127461] [PMID: 32755679]
[3]
Nakanishi, H. Cathepsin regulation on microglial function. Biochim. Biophys. Acta. Proteins Proteomics, 2020, 1868(9), 140465.
[http://dx.doi.org/10.1016/j.bbapap.2020.140465] [PMID: 32526473]
[4]
Felbor, U.; Kessler, B.; Mothes, W.; Goebel, H.H.; Ploegh, H.L.; Bronson, R.T.; Olsen, B.R. Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc. Natl. Acad. Sci. USA, 2002, 99(12), 7883-7888.
[http://dx.doi.org/10.1073/pnas.112632299] [PMID: 12048238]
[5]
Stahl, S.; Reinders, Y.; Asan, E.; Mothes, W.; Conzelmann, E.; Sickmann, A.; Felbor, U. Proteomic analysis of cathepsin B- and L-deficient mouse brain lysosomes. Biochim. Biophys. Acta, 2007, 1774(10), 1237-1246.
[http://dx.doi.org/10.1016/j.bbapap.2007.07.004] [PMID: 17765022]
[6]
Gan, L.; Ye, S.; Chu, A.; Anton, K.; Yi, S.; Vincent, V.A.; von Schack, D.; Chin, D.; Murray, J.; Lohr, S.; Patthy, L.; Gonzalez-Zulueta, M.; Nikolich, K.; Urfer, R. Identification of cathepsin B as a mediator of neuronal death induced by Abeta-activated microglial cells using a functional genomics approach. J. Biol. Chem., 2004, 279(7), 5565-5572.
[http://dx.doi.org/10.1074/jbc.M306183200] [PMID: 14612454]
[7]
Im, E.; Venkatakrishnan, A.; Kazlauskas, A. Cathepsin B regulates the intrinsic angiogenic threshold of endothelial cells. Mol. Biol. Cell, 2005, 16(8), 3488-3500.
[http://dx.doi.org/10.1091/mbc.e04-11-1029] [PMID: 15901832]
[8]
Lerch, M.M.; Halangk, W. Human pancreatitis and the role of cathepsin B. Gut, 2006, 55(9), 1228-1230.
[http://dx.doi.org/10.1136/gut.2006.092114] [PMID: 16905693]
[9]
Yan, S.; Sloane, B.F. Molecular regulation of human cathepsin B: Implication in pathologies. Biol. Chem., 2003, 384(6), 845-854.
[http://dx.doi.org/10.1515/BC.2003.095] [PMID: 12887051]
[10]
Aggarwal, N.; Sloane, B.F.; Cathepsin, B. Multiple roles in cancer. Proteomics Clin. Appl., 2014, 8(5-6), 427-437.
[http://dx.doi.org/10.1002/prca.201300105] [PMID: 24677670]
[11]
Kumar, A.; Singh, A. Ekavali, A review on Alzheimer’s disease pathophysiology and its management: An update. Pharmacol. Rep., 2015, 67(2), 195-203.
[http://dx.doi.org/10.1016/j.pharep.2014.09.004] [PMID: 25712639]
[12]
Cummings, J.L.; Vinters, H.V.; Cole, G.M.; Khachaturian, Z.S. Alzheimer’s disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology, 1998, 51(1)(Suppl. 1), S2-S17.
[http://dx.doi.org/10.1212/WNL.51.1_Suppl_1.S2] [PMID: 9674758]
[13]
Hook, G.; Hook, V.Y.; Kindy, M. Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer’s disease therapeutics. Biol. Chem., 2007, 388(9), 979-983.
[http://dx.doi.org/10.1515/BC.2007.117] [PMID: 17696783]
[14]
Hook, V.; Hook, G.; Kindy, M. Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce beta-amyloid related to Alzheimer’s disease. Biol. Chem., 2010, 391(8), 861-872.
[http://dx.doi.org/10.1515/bc.2010.110] [PMID: 20536395]
[15]
Kindy, M.S.; Yu, J.; Zhu, H.; El-Amouri, S.S.; Hook, V.; Hook, G.R. Deletion of the cathepsin B gene improves memory deficits in a transgenic Alzheimer’s disease mouse model expressing AβPP containing the wild-type β-secretase site sequence. J. Alzheimers Dis., 2012, 29(4), 827-840.
[http://dx.doi.org/10.3233/JAD-2012-111604] [PMID: 22337825]
[16]
Cataldo, A.M.; Nixon, R.A. Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc. Natl. Acad. Sci. USA, 1990, 87(10), 3861-3865.
[http://dx.doi.org/10.1073/pnas.87.10.3861] [PMID: 1692625]
[17]
Umeda, T.; Tomiyama, T.; Sakama, N.; Tanaka, S.; Lambert, M.P.; Klein, W.L.; Mori, H. Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo . J. Neurosci. Res., 2011, 89(7), 1031-1042.
[http://dx.doi.org/10.1002/jnr.22640] [PMID: 21488093]
[18]
Shao, Q.H.; Zhang, X.L.; Yang, P.F.; Yuan, Y.H.; Chen, N.H. Amyloidogenic proteins associated with neurodegenerative diseases activate the NLRP3 inflammasome. Int. Immunopharmacol., 2017, 49, 155-160.
[http://dx.doi.org/10.1016/j.intimp.2017.05.027] [PMID: 28595078]
[19]
Llorente, P.; Kristen, H.; Sastre, I.; Toledano-Zaragoza, A.; Aldudo, J.; Recuero, M.; Bullido, M.J. A free radical-generating system regulates amyloid oligomers: Involvement of cathepsin B. J. Alzheimers Dis., 2018, 66(4), 1397-1408.
[http://dx.doi.org/10.3233/JAD-170159] [PMID: 30400084]
[20]
Nakanishi, H.; Tominaga, K.; Amano, T.; Hirotsu, I.; Inoue, T.; Yamamoto, K. Age-related changes in activities and localizations of cathepsins D, E, B, and L in the rat brain tissues. Exp. Neurol., 1994, 126(1), 119-128.
[http://dx.doi.org/10.1006/exnr.1994.1048] [PMID: 8157122]
[21]
Hsu, A.; Podvin, S.; Hook, V. Lysosomal cathepsin protease gene expression profiles in the human brain during normal development. J. Mol. Neurosci., 2018, 65(4), 420-431.
[http://dx.doi.org/10.1007/s12031-018-1110-6] [PMID: 30008074]
[22]
Ferrara, M.; Wojcik, F.; Rhaissi, H.; Mordier, S.; Roux, M.P.; Béchet, D. Gene structure of mouse cathepsin B. FEBS Lett., 1990, 273(1-2), 195-199.
[http://dx.doi.org/10.1016/0014-5793(90)81083-Z] [PMID: 2226854]
[23]
Pungercar, J.R.; Caglic, D.; Sajid, M.; Dolinar, M.; Vasiljeva, O.; Pozgan, U.; Turk, D.; Bogyo, M.; Turk, V.; Turk, B. Autocatalytic processing of procathepsin B is triggered by proenzyme activity. FEBS J., 2009, 276(3), 660-668.
[http://dx.doi.org/10.1111/j.1742-4658.2008.06815.x] [PMID: 19143833]
[24]
Mort, J.S.; Buttle, D.J.; Cathepsin, B. Int. J. Biochem. Cell Biol., 1997, 29(5), 715-720.
[http://dx.doi.org/10.1016/S1357-2725(96)00152-5] [PMID: 9251238]
[25]
Stoka, V.; Turk, V.; Turk, B. Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res. Rev., 2016, 32, 22-37.
[http://dx.doi.org/10.1016/j.arr.2016.04.010] [PMID: 27125852]
[26]
Katunuma, N. Posttranslational processing and modification of cathepsins and cystatins. J. Signal Transduct., 2010, 2010, 375345.
[http://dx.doi.org/10.1155/2010/375345] [PMID: 21637353]
[27]
Mach, L.; Mort, J.S.; Glössl, J. Maturation of human procathepsin B. Proenzyme activation and proteolytic processing of the precursor to the mature proteinase, in vitro , are primarily unimolecular processes. J. Biol. Chem., 1994, 269(17), 13030-13035.
[http://dx.doi.org/10.1016/S0021-9258(18)99979-5] [PMID: 8175723]
[28]
Hook, V.; Yoon, M.; Mosier, C.; Ito, G.; Podvin, S.; Head, B.P.; Rissman, R.; O’Donoghue, A.J.; Hook, G. Cathepsin B in neurodegeneration of Alzheimer’s disease, traumatic brain injury, and related brain disorders. Biochim. Biophys. Acta. Proteins Proteomics, 2020, 1868(8), 140428.
[http://dx.doi.org/10.1016/j.bbapap.2020.140428] [PMID: 32305689]
[29]
Nishimura, Y.; Kato, K. Intracellular transport and processing of lysosomal cathepsin B. Biochem. Biophys. Res. Commun., 1987, 148(1), 254-259.
[http://dx.doi.org/10.1016/0006-291X(87)91103-X] [PMID: 3675577]
[30]
Cavallo-Medved, D.; Sloane, B.F.; Moin, K. K.; Cathepsin B. In: Choi S. ed. Encyclopedia of Signaling Molecules. New York, NY: Springer, 2016, pp. 1-17.
[31]
Menting, K.W.; Claassen, J.A. β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front. Aging Neurosci., 2014, 6, 165.
[http://dx.doi.org/10.3389/fnagi.2014.00165] [PMID: 25100992]
[32]
Vassar, R.; Bennett, B.D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E.A.; Denis, P.; Teplow, D.B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M.A.; Biere, A.L.; Curran, E.; Burgess, T.; Louis, J.C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 1999, 286(5440), 735-741.
[http://dx.doi.org/10.1126/science.286.5440.735] [PMID: 10531052]
[33]
Perlenfein, T.J.; Murphy, R.M. A mechanistic model to predict effects of cathepsin B and cystatin C on β-amyloid aggregation and degradation. J. Biol. Chem., 2017, 292(51), 21071-21082.
[http://dx.doi.org/10.1074/jbc.M117.811448] [PMID: 29046353]
[34]
Tomita, T. Secretase inhibitors and modulators for Alzheimer’s disease treatment. Expert Rev. Neurother., 2009, 9(5), 661-679.
[http://dx.doi.org/10.1586/ern.09.24] [PMID: 19402777]
[35]
Hook, V.Y.; Toneff, T.; Aaron, W.; Yasothornsrikul, S.; Bundey, R.; Reisine, T. Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: Evidence for multiple cysteine proteolytic activities in distinct pathways for beta-secretase activity in chromaffin vesicles. J. Neurochem., 2002, 81(2), 237-256.
[http://dx.doi.org/10.1046/j.1471-4159.2002.00794.x] [PMID: 12064471]
[36]
Hook, V.; Toneff, T.; Bogyo, M.; Greenbaum, D.; Medzihradszky, K.F.; Neveu, J.; Lane, W.; Hook, G.; Reisine, T. Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: Evidence for cathepsin B as a candidate beta-secretase of Alzheimer’s disease. Biol. Chem., 2005, 386(9), 931-940.
[http://dx.doi.org/10.1515/BC.2005.108] [PMID: 16164418]
[37]
Hook, G.; Jacobsen, J.S.; Grabstein, K.; Kindy, M.; Hook, V. Cathepsin B is a new drug target for traumatic brain injury therapeutics: Evidence for E64d as a promising lead drug candidate. Front. Neurol., 2015, 6, 178.
[http://dx.doi.org/10.3389/fneur.2015.00178] [PMID: 26388830]
[38]
Hook, V.Y. Protease pathways in peptide neurotransmission and neurodegenerative diseases. Cell. Mol. Neurobiol., 2006, 26(4-6), 449-469.
[http://dx.doi.org/10.1007/s10571-006-9047-7] [PMID: 16724274]
[39]
Hook, V.Y.; Kindy, M.; Reinheckel, T.; Peters, C.; Hook, G. Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein. Biochem. Biophys. Res. Commun., 2009, 386(2), 284-288.
[http://dx.doi.org/10.1016/j.bbrc.2009.05.131] [PMID: 19501042]
[40]
Wang, C.; Telpoukhovskaia, M.A.; Bahr, B.A.; Chen, X.; Gan, L. Endo-lysosomal dysfunction: A converging mechanism in neurodegenerative diseases. Curr. Opin. Neurobiol., 2018, 48, 52-58.
[http://dx.doi.org/10.1016/j.conb.2017.09.005] [PMID: 29028540]
[41]
Viana, G.M.; Gonzalez, E.A.; Alvarez, M.M.P.; Cavalheiro, R.P.; do Nascimento, C.C.; Baldo, G.; D’Almeida, V.; de Lima, M.A.; Pshezhetsky, A.V.; Nader, H.B. Cathepsin B-associated activation of amyloidogenic pathway in murine mucopolysaccharidosis type I brain cortex. Int. J. Mol. Sci., 2020, 21(4), E1459.
[http://dx.doi.org/10.3390/ijms21041459] [PMID: 32093427]
[42]
Hook, V.Y. Unique neuronal functions of cathepsin L and cathepsin B in secretory vesicles: Biosynthesis of peptides in neurotransmission and neurodegenerative disease. Biol. Chem., 2006, 387(10-11), 1429-1439.
[http://dx.doi.org/10.1515/BC.2006.179] [PMID: 17081116]
[43]
Hook, V.Y.; Reisine, T.D. Cysteine proteases are the major beta-secretase in the regulated secretory pathway that provides most of the beta-amyloid in Alzheimer’s disease: Role of BACE 1 in the constitutive secretory pathway. J. Neurosci. Res., 2003, 74(3), 393-405.
[http://dx.doi.org/10.1002/jnr.10784] [PMID: 14598316]
[44]
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), 1456-1460.
[http://dx.doi.org/10.1073/pnas.97.4.1456] [PMID: 10677483]
[45]
Wang, M.; Li, Y.; Ni, C.; Song, G. Honokiol attenuates oligomeric amyloid β1-42-induced Alzheimer’s disease in mice through attenuating mitochondrial apoptosis and inhibiting the nuclear factor Kappa-B signaling pathway. Cell. Physiol. Biochem., 2017, 43(1), 69-81.
[http://dx.doi.org/10.1159/000480320] [PMID: 28848085]
[46]
Sankaranarayanan, S.; Price, E.A.; Wu, G.; Crouthamel, M.C.; Shi, X.P.; Tugusheva, K.; Tyler, K.X.; Kahana, J.; Ellis, J.; Jin, L.; Steele, T.; Stachel, S.; Coburn, C.; Simon, A.J. 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), 957-969.
[http://dx.doi.org/10.1124/jpet.107.130039] [PMID: 18156464]
[47]
Jawhar, S.; Wirths, O.; Bayer, T.A. Pyroglutamate amyloid-β (Aβ): A hatchet man in Alzheimer disease. J. Biol. Chem., 2011, 286(45), 38825-38832.
[http://dx.doi.org/10.1074/jbc.R111.288308] [PMID: 21965666]
[48]
Sun, B.; Zhou, Y.; Halabisky, B.; Lo, I.; Cho, S.H.; Mueller-Steiner, S.; Devidze, N.; Wang, X.; Grubb, A.; Gan, L. Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer’s disease. Neuron, 2008, 60(2), 247-257.
[http://dx.doi.org/10.1016/j.neuron.2008.10.001] [PMID: 18957217]
[49]
Perez-Garmendia, R.; Gevorkian, G. Pyroglutamate-modified amyloid beta peptides: Emerging targets for Alzheimer’s disease immunotherapy. Curr. Neuropharmacol., 2013, 11(5), 491-498.
[http://dx.doi.org/10.2174/1570159X11311050004] [PMID: 24403873]
[50]
Hook, G.; Yu, J.; Toneff, T.; Kindy, M.; Hook, V. Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer’s disease therapeutic. J. Alzheimers Dis., 2014, 41(1), 129-149.
[http://dx.doi.org/10.3233/JAD-131370] [PMID: 24595198]
[51]
Iwatsubo, T.; Saido, T.C.; Mann, D.M.; Lee, V.M.; Trojanowski, J.Q. Full-length amyloid-f3(1-42(43)) and amino-terminally modified and truncated amyloid-(42(43) deposit in diffuse plaques. Am. J. Pathol., 1996, 149(6), 1823-1830.
[52]
De Kimpe, L.; Scheper, W. From alpha to omega with Abeta: Targeting the multiple molecular appearances of the pathogenic peptide in Alzheimer’s disease. Curr. Med. Chem., 2010, 17(3), 198-212.
[http://dx.doi.org/10.2174/092986710790149765] [PMID: 20214563]
[53]
Wirths, O.; Erck, C.; Martens, H.; Harmeier, A.; Geumann, C.; Jawhar, S.; Kumar, S.; Multhaup, G.; Walter, J.; Ingelsson, M.; Degerman-Gunnarsson, M.; Kalimo, H.; Huitinga, I.; Lannfelt, L.; Bayer, T.A. Identification of low molecular weight pyroglutamate Abeta oligomers in Alzheimer disease: A novel tool for therapy and diagnosis. J. Biol. Chem., 2010, 285(53), 41517-41524.
[http://dx.doi.org/10.1074/jbc.M110.178707] [PMID: 20971852]
[54]
Frost, J.L.; Le, K.X.; Cynis, H.; Ekpo, E.; Kleinschmidt, M.; Palmour, R.M.; Ervin, F.R.; Snigdha, S.; Cotman, C.W.; Saido, T.C.; Vassar, R.J.; St George-Hyslop, P.; Ikezu, T.; Schilling, S.; Demuth, H.U.; Lemere, C.A. Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am. J. Pathol., 2013, 183(2), 369-381.
[http://dx.doi.org/10.1016/j.ajpath.2013.05.005] [PMID: 23747948]
[55]
Wang, P.N.; Lin, K.J.; Liu, H.C.; Andreasson, U.; Blennow, K.; Zetterberg, H.; Yang, S.Y. Plasma pyroglutamate-modified amyloid beta differentiates amyloid pathology. Alzheimers Dement. (Amst.), 2020, 12(1), e12029.
[http://dx.doi.org/10.1002/dad2.12029] [PMID: 32363230]
[56]
Russo, C.; Violani, E.; Salis, S.; Venezia, V.; Dolcini, V.; Damonte, G.; Benatti, U.; D’Arrigo, C.; Patrone, E.; Carlo, P.; Schettini, G. Pyroglutamate-modified amyloid beta-peptides--AbetaN3(pE)--strongly affect cultured neuron and astrocyte survival. J. Neurochem., 2002, 82(6), 1480-1489.
[http://dx.doi.org/10.1046/j.1471-4159.2002.01107.x] [PMID: 12354296]
[57]
Moro, M.L.; Phillips, A.S.; Gaimster, K.; Paul, C.; Mudher, A.; Nicoll, J.A.R.; Boche, D. Pyroglutamate and isoaspartate modified amyloid-beta in ageing and Alzheimer’s disease. Acta Neuropathol. Commun., 2018, 6(1), 3.
[http://dx.doi.org/10.1186/s40478-017-0505-x] [PMID: 29298722]
[58]
DiSabato, D.J.; Quan, N.; Godbout, J.P. Neuroinflammation: The devil is in the details. J. Neurochem., 2016, 139(Suppl. 2), 136-153.
[http://dx.doi.org/10.1111/jnc.13607] [PMID: 26990767]
[59]
Nakanishi, H. Neuronal and microglial cathepsins in aging and age-related diseases. Ageing Res. Rev., 2003, 2(4), 367-381.
[http://dx.doi.org/10.1016/S1568-1637(03)00027-8] [PMID: 14522241]
[60]
Hornung, V.; Latz, E. Critical functions of priming and lysosomal damage for NLRP3 activation. Eur. J. Immunol., 2010, 40(3), 620-623.
[http://dx.doi.org/10.1002/eji.200940185] [PMID: 20201015]
[61]
Kelley, N.; Jeltema, D.; Duan, Y.; He, Y. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int. J. Mol. Sci., 2019, 20(13), E3328.
[http://dx.doi.org/10.3390/ijms20133328] [PMID: 31284572]
[62]
Hafner-Bratkovič, I.; Benčina, M.; Fitzgerald, K.A.; Golenbock, D.; Jerala, R. NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity. Cell. Mol. Life Sci., 2012, 69(24), 4215-4228.
[http://dx.doi.org/10.1007/s00018-012-1140-0] [PMID: 22926439]
[63]
Nakanishi, H. Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging. Neural Regen. Res., 2020, 15(1), 25-29.
[http://dx.doi.org/10.4103/1673-5374.264444] [PMID: 31535638]
[64]
Hoegen, T.; Tremel, N.; Klein, M.; Angele, B.; Wagner, H.; Kirschning, C.; Pfister, H.W.; Fontana, A.; Hammerschmidt, S.; Koedel, U. The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release. J. Immunol., 2011, 187(10), 5440-5451.
[http://dx.doi.org/10.4049/jimmunol.1100790] [PMID: 22003197]
[65]
Zahid, A.; Li, B.; Kombe, A.J.K.; Jin, T.; Tao, J. Pharmacological inhibitors of the NLRP3 inflammasome. Front. Immunol., 2019, 10, 2538.
[http://dx.doi.org/10.3389/fimmu.2019.02538] [PMID: 31749805]
[66]
Rajaram, K.; Nelson, D.E. Chlamydia muridarum infection of macrophages elicits bactericidal nitric oxide production via reactive oxygen species and cathepsin B. Infect. Immun., 2015, 83(8), 3164-3175.
[http://dx.doi.org/10.1128/IAI.00382-15] [PMID: 26015483]
[67]
Liu, T.; Zhang, L.; Joo, D.; Sun, S.C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther., 2017, 2, 2.
[http://dx.doi.org/10.1038/sigtrans.2017.23] [PMID: 29158945]
[68]
Terada, K.; Yamada, J.; Hayashi, Y.; Wu, Z.; Uchiyama, Y.; Peters, C.; Nakanishi, H. Involvement of cathepsin B in the processing and secretion of interleukin-1beta in chromogranin A-stimulated microglia. Glia, 2010, 58(1), 114-124.
[http://dx.doi.org/10.1002/glia.20906] [PMID: 19544382]
[69]
Sun, L.; Wu, Z.; Hayashi, Y.; Peters, C.; Tsuda, M.; Inoue, K.; Nakanishi, H. Microglial cathepsin B contributes to the initiation of peripheral inflammation-induced chronic pain. J. Neurosci., 2012, 32(33), 11330-11342.
[http://dx.doi.org/10.1523/JNEUROSCI.0677-12.2012] [PMID: 22895716]
[70]
Wu, Z.; Sun, L.; Hashioka, S.; Yu, S.; Schwab, C.; Okada, R.; Hayashi, Y.; McGeer, P.L.; Nakanishi, H. Differential pathways for interleukin-1β production activated by chromogranin A and amyloid β in microglia. Neurobiol. Aging, 2013, 34(12), 2715-2725.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.05.018] [PMID: 23831373]
[71]
Kingham, P.J.; Pocock, J.M. Microglial secreted cathepsin B induces neuronal apoptosis. J. Neurochem., 2001, 76(5), 1475-1484.
[http://dx.doi.org/10.1046/j.1471-4159.2001.00146.x] [PMID: 11238732]
[72]
Ni, J.; Wu, Z.; Peterts, C.; Yamamoto, K.; Qing, H.; Nakanishi, H. The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage. J. Neurosci., 2015, 35(36), 12488-12501.
[http://dx.doi.org/10.1523/JNEUROSCI.1599-15.2015] [PMID: 26354916]
[73]
Shi, Z.M.; Han, Y.W.; Han, X.H.; Zhang, K.; Chang, Y.N.; Hu, Z.M.; Qi, H.X.; Ting, C.; Zhen, Z.; Hong, W. Upstream regulators and downstream effectors of NF-κB in Alzheimer’s disease. J. Neurol. Sci., 2016, 366, 127-134.
[http://dx.doi.org/10.1016/j.jns.2016.05.022] [PMID: 27288790]
[74]
Lawrence, T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb. Perspect. Biol., 2009, 1(6), a001651.
[http://dx.doi.org/10.1101/cshperspect.a001651] [PMID: 20457564]
[75]
McGuire, K.A.; Barlan, A.U.; Griffin, T.M.; Wiethoff, C.M. Adenovirus type 5 rupture of lysosomes leads to cathepsin B-dependent mitochondrial stress and production of reactive oxygen species. J. Virol., 2011, 85(20), 10806-10813.
[http://dx.doi.org/10.1128/JVI.00675-11] [PMID: 21835790]
[76]
Coskun, P.E.; Beal, M.F.; Wallace, D.C. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc. Natl. Acad. Sci. USA, 2004, 101(29), 10726-10731.
[http://dx.doi.org/10.1073/pnas.0403649101] [PMID: 15247418]
[77]
Kanki, T.; Ohgaki, K.; Gaspari, M.; Gustafsson, C.M.; Fukuoh, A.; Sasaki, N.; Hamasaki, N.; Kang, D. Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Mol. Cell. Biol., 2004, 24(22), 9823-9834.
[http://dx.doi.org/10.1128/MCB.24.22.9823-9834.2004] [PMID: 15509786]
[78]
Nakanishi, H.; Wu, Z. Microglia-aging: Roles of microglial lysosome- and mitochondria-derived reactive oxygen species in brain aging. Behav. Brain Res., 2009, 201(1), 1-7.
[http://dx.doi.org/10.1016/j.bbr.2009.02.001] [PMID: 19428609]
[79]
Kang, I.; Chu, C.T.; Kaufman, B.A. The mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms. FEBS Lett., 2018, 592(5), 793-811.
[http://dx.doi.org/10.1002/1873-3468.12989] [PMID: 29364506]
[80]
Matsushima, Y.; Goto, Y.; Kaguni, L.S. Mitochondrial Lon protease regulates mitochondrial DNA copy number and transcription by selective degradation of mitochondrial transcription factor A (TFAM). Proc. Natl. Acad. Sci. USA, 2010, 107(43), 18410-18415.
[http://dx.doi.org/10.1073/pnas.1008924107] [PMID: 20930118]
[81]
Ni, J.; Wu, Z.; Stoka, V.; Meng, J.; Hayashi, Y.; Peters, C.; Qing, H.; Turk, V.; Nakanishi, H. Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. Aging Cell, 2019, 18(1), e12856.
[http://dx.doi.org/10.1111/acel.12856] [PMID: 30575263]
[82]
Hayashi, Y.; Yoshida, M.; Yamato, M.; Ide, T.; Wu, Z.; Ochi-Shindou, M.; Kanki, T.; Kang, D.; Sunagawa, K.; Tsutsui, H.; Nakanishi, H. Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J. Neurosci., 2008, 28(34), 8624-8634.
[http://dx.doi.org/10.1523/JNEUROSCI.1957-08.2008] [PMID: 18716221]
[83]
Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: Design and clinical applications. Nat. Rev. Drug Discov., 2008, 7(3), 255-270.
[http://dx.doi.org/10.1038/nrd2468] [PMID: 18219308]
[84]
Poreba, M. Protease-activated prodrugs: Strategies, challenges, and future directions. FEBS J., 2020, 287(10), 1936-1969.
[http://dx.doi.org/10.1111/febs.15227] [PMID: 31991521]
[85]
Choi, K.Y.; Swierczewska, M.; Lee, S.; Chen, X. Protease-activated drug development. Theranostics, 2012, 2(2), 156-178.
[http://dx.doi.org/10.7150/thno.4068] [PMID: 22400063]
[86]
Siveen, K.S.; Kuttan, G. Effect of amentoflavone, a phenolic component from Biophytum sensitivum, on cell cycling and apoptosis of B16F-10 melanoma cells. J. Environ. Pathol. Toxicol. Oncol., 2011, 30(4), 301-309.
[http://dx.doi.org/10.1615/JEnvironPatholToxicolOncol.v30.i4.30] [PMID: 22181979]
[87]
Bais, S.; Abrol, N. Review on chemistry and pharmacological potential of amentoflavone. Curr. Res. Neurosci., 2015, 6(1), 16-22.
[http://dx.doi.org/10.3923/crn.2016.16.22]
[88]
Zeng, G.Z.; Pan, X.L.; Tan, N.H.; Xiong, J.; Zhang, Y.M. Natural biflavones as novel inhibitors of cathepsin B and K. Eur. J. Med. Chem., 2006, 41(11), 1247-1252.
[http://dx.doi.org/10.1016/j.ejmech.2006.06.002] [PMID: 16828525]
[89]
Pan, X.; Tan, N.; Zeng, G.; Zhang, Y.; Jia, R. Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B. Bioorg. Med. Chem., 2005, 13(20), 5819-5825.
[http://dx.doi.org/10.1016/j.bmc.2005.05.071] [PMID: 16084098]
[90]
Repnik, U.; Stoka, V.; Turk, V.; Turk, B. Lysosomes and lysosomal cathepsins in cell death. Biochim. Biophys. Acta, 2012, 1824(1), 22-33.
[http://dx.doi.org/10.1016/j.bbapap.2011.08.016] [PMID: 21914490]
[91]
Buttle, D.J.; Murata, M.; Knight, C.G.; Barrett, A.J. CA074 methyl ester: A proinhibitor for intracellular cathepsin B. Arch. Biochem. Biophys., 1992, 299(2), 377-380.
[http://dx.doi.org/10.1016/0003-9861(92)90290-D] [PMID: 1444478]
[92]
Hook, V.Y.; Kindy, M.; Hook, G. Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. J. Biol. Chem., 2008, 283(12), 7745-7753.
[http://dx.doi.org/10.1074/jbc.M708362200] [PMID: 18184658]
[93]
Murata, M.; Miyashita, S.; Yokoo, C.; Tamai, M.; Hanada, K.; Hatayama, K.; Towatari, T.; Nikawa, T.; Katunuma, N. Novel epoxysuccinyl peptides. Selective inhibitors of cathepsin B, in vitro . FEBS Lett., 1991, 280(2), 307-310.
[http://dx.doi.org/10.1016/0014-5793(91)80318-W] [PMID: 2013328]
[94]
Yamamoto, A.; Hara, T.; Tomoo, K.; Ishida, T.; Fujii, T.; Hata, Y.; Murata, M.; Kitamura, K. Binding mode of CA074, a specific irreversible inhibitor, to bovine cathepsin B as determined by X-ray crystal analysis of the complex. J. Biochem., 1997, 121(5), 974-977.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a021682] [PMID: 9192742]
[95]
Towatari, T.; Nikawa, T.; Murata, M.; Yokoo, C.; Tamai, M.; Hanada, K.; Katunuma, N. Novel epoxysuccinyl peptides. A selective inhibitor of cathepsin B, in vivo . FEBS Lett., 1991, 280(2), 311-315.
[http://dx.doi.org/10.1016/0014-5793(91)80319-X] [PMID: 2013329]
[96]
Steverding, D. The cathepsin b-selective inhibitors CA-074 and CA-074Me inactivate cathepsin L under reducing conditions. Open Enzyme Inhib. J., 2011, 4(1), 11-16.
[http://dx.doi.org/10.2174/1874940201104010011]
[97]
Yamamoto, A.; Tomoo, K.; Hara, T.; Murata, M.; Kitamura, K.; Ishida, T. Substrate specificity of bovine cathepsin B and its inhibition by CA074, based on crystal structure refinement of the complex. J. Biochem., 2000, 127(4), 635-643.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a022651] [PMID: 10739956]
[98]
Musil, D.; Zucic, D.; Turk, D.; Engh, R.A.; Mayr, I.; Huber, R.; Popovic, T.; Turk, V.; Towatari, T.; Katunuma, N. The refined 2.15 A X-ray crystal structure of human liver cathepsin B: The structural basis for its specificity. EMBO J., 1991, 10(9), 2321-2330.
[99]
Klein, D.M.; Felsenstein, K.M.; Brenneman, D.E. Cathepsins B and L differentially regulate amyloid precursor protein processing. J. Pharmacol. Exp. Ther., 2009, 328(3), 813-821.
[http://dx.doi.org/10.1124/jpet.108.147082] [PMID: 19064719]
[100]
Montaser, M.; Lalmanach, G.; Mach, L. CA-074, but not its methyl ester CA-074Me, is a selective inhibitor of cathepsin B within living cells. Biol. Chem., 2002, 383(7-8), 1305-1308.
[http://dx.doi.org/10.1515/BC.2002.147] [PMID: 12437121]
[101]
Cho, K.; Yoon, S.Y.; Choi, J.E.; Kang, H.J.; Jang, H.Y.; Kim, D.H. CA-074Me, a cathepsin B inhibitor, decreases APP accumulation and protects primary rat cortical neurons treated with okadaic acid. Neurosci. Lett., 2013, 548, 222-227.
[http://dx.doi.org/10.1016/j.neulet.2013.05.056] [PMID: 23748042]
[102]
Hook, G.; Hook, V.; Kindy, M. The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer’s disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity. J. Alzheimers Dis., 2011, 26(2), 387-408.
[http://dx.doi.org/10.3233/JAD-2011-110101] [PMID: 21613740]
[103]
Hashida, S.; Towatari, T.; Kominami, E.; Katunuma, N. Inhibitions by E-64 derivatives of rat liver cathepsin B and cathepsin L in vitro and in vivo . J. Biochem., 1980, 88(6), 1805-1811.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a133155] [PMID: 7462205]
[104]
Hook, G.R.; Yu, J.; Sipes, N.; Pierschbacher, M.D.; Hook, V.; Kindy, M.S. The cysteine protease cathepsin B is a key drug target and cysteine protease inhibitors are potential therapeutics for traumatic brain injury. J. Neurotrauma, 2014, 31(5), 515-529.
[http://dx.doi.org/10.1089/neu.2013.2944] [PMID: 24083575]
[105]
Tamai, M.; Matsumoto, K.; Omura, S.; Koyama, I.; Ozawa, Y.; Hanada, K. in vitro and in vivo inhibition of cysteine proteinases by EST, a new analog of E-64. J. Pharmacobiodyn., 1986, 9(8), 672-677.
[http://dx.doi.org/10.1248/bpb1978.9.672] [PMID: 3023601]
[106]
Yoon, M.C.; Solania, A.; Jiang, Z.; Christy, M.P.; Podvin, S.; Mosier, C.; Lietz, C.B.; Ito, G.; Gerwick, W.H.; Wolan, D.W.; Hook, G.; O’Donoghue, A.J.; Hook, V. Selective neutral pH inhibitor of Cathepsin B designed based on cleavage preferences at cytosolic and lysosomal pH conditions. ACS Chem. Biol., 2021, 16(9), 1628-1643.
[http://dx.doi.org/10.1021/acschembio.1c00138] [PMID: 34416110]
[107]
Poreba, M.; Groborz, K.; Vizovisek, M.; Maruggi, M.; Turk, D.; Turk, B.; Powis, G.; Drag, M.; Salvesen, G.S. Fluorescent probes towards selective cathepsin B detection and visualization in cancer cells and patient samples. Chem. Sci. (Camb.), 2019, 10(36), 8461-8477.
[http://dx.doi.org/10.1039/C9SC00997C] [PMID: 31803426]
[108]
Dai, Z.; Cheng, Q.; Zhang, Y. Rational design of a humanized antibody inhibitor of cathepsin B. Biochemistry, 2020, 59(14), 1420-1427.
[http://dx.doi.org/10.1021/acs.biochem.0c00046] [PMID: 32212642]
[109]
Maximiano, S.; Magalhães, P.; Guerreiro, M.P.; Morgado, M. Trastuzumab in the treatment of breast cancer. BioDrugs, 2016, 30(2), 75-86.
[http://dx.doi.org/10.1007/s40259-016-0162-9] [PMID: 26892619]

Rights & Permissions Print Cite
Article Metrics
20
© 2024 Bentham Science Publishers | Privacy Policy