The protein encoded by this gene is a lysosomalcysteine protease composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. It is a member of the peptidase C1 family. At least five transcript variants encoding the same protein have been found for this gene.
A wide array of diseases result in elevated levels of cathepsin B, which causes numerous pathological processes including cell death, inflammation, and production of toxic peptides. Focusing on neurological diseases, cathepsin B gene knockout studies in an epileptic rodent model have shown cathepsin B causes a significant amount of the apoptotic cell death that occurs as a result of inducing epilepsy. Cathepsin B inhibitor treatment of rats in which a seizure was induced resulted in improved neurological scores, learning ability and much reduced neuronal cell death and pro-apoptotic cell death peptides. Similarly, cathepsin B gene knockout and cathepsin B inhibitor treatment studies in traumatic brain injury mouse models have shown cathepsin B to be key to causing the resulting neuromuscular dysfunction, memory loss, neuronal cell death and increased production of pro-necrotic and pro-apoptotic cell death peptides. In ischemic non-human primate and rodent models, cathepsin B inhibitor treatment prevented a significant loss of brain neurons, especially in the hippocampus. In a streptococcus pneumoniae meningitis rodent model, cathepsin B inhibitor treatment greatly improved the clinical course of the infection and reduced brain inflammation and inflammatory Interleukin-1beta (IL1-beta) and tumor necrosis factor-alpha (TNFalpha). In a transgenic Alzheimer's disease (AD) animal model expressing human amyloid precursor protein (APP) containing the wild-type beta-secretase site sequence found in most AD patients or in guinea pigs, which are a natural model of human wild-type APP processing, genetically deleting the cathepsin B gene or chemically inhibiting cathepsin B brain activity resulted in a significant improvement in the memory deficits that develop in such mice and reduces levels of neurotoxic full-length Abeta(1-40/42) and the particularly pernicious pyroglutamate Abeta(3-40/42), which are thought to cause the disease. In a non-transgenic senescence-accelerated mouse strain, which also has APP containing the wild-type beta-secretase site sequence, treatment with bilobalide, which is an extract of Ginko biloba leaves, also lowered brain Abeta by inhibiting cathepsin B. Moreover, siRNA silencing or chemically inhibiting cathepsin B in primary rodent hippocampal cells or bovine chromaffin cells, which have human wild-type beta-secretase activity, reduces secretion of Abeta by the regulated secretory pathway.
^Houseweart MK, Pennacchio LA, Vilaythong A, Peters C, Noebels JL, Myers RM (2003). "Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1)". J. Neurobiol.56 (4): 315–27. doi:10.1002/neu.10253. PMID12918016.
^Ni H, Ren SY, Zhang LL, Sun Q, Tian T, Feng X (2013). "Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus". Toxicol. Lett.217 (2): 162–9. doi:10.1016/j.toxlet.2012.12.010. PMID23266720.
^Luo CL, Chen XP, Yang R, Sun YX, Li QQ, Bao HJ, Cao QQ, Ni H, Qin ZH, Tao LY (2010). "Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway". J Neurosci Res88 (13): 2847–58. doi:10.1002/jnr.22453. PMID20653046.
^Yoshida M, Yamashima T, Zhao L, Tsuchiya K, Kohda Y, Tonchev AB, Matsuda M, Kominami E (2002). "Primate neurons show different vulnerability to transient ischemia and response to cathepsin inhibition". Acta Neuropathol (Berl)104 (3): 267–72. doi:10.1007/s00401-002-0554-4. PMID12172912.
^Tsuchiya K, Kohda Y, Yoshida M, Zhao L, Ueno T, Yamashita J, Yoshioka T, Kominami E, Yamashima T (1999). "Postictal blockade of ischemic hippocampal neuronal death in primates using selective cathepsin inhibitors". Exp Neurol155 (2): 187–94. doi:10.1006/exnr.1998.6988. PMID10072294.
^Tsubokawa T, Yamaguchi-Okada M, Calvert JW, Solaroglu I, Shimamura N, Yata K, Zhang JH (2006). "Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats". J Neurosci Res84 (4): 832–40. doi:10.1002/jnr.20977. PMID16802320.
^Hoegen T, Tremel N, Klein M, Angele B, Wagner H, Kirschning C, Pfister HW, Fontana A, Hammerschmidt S, Koedel U (2011). "The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release". J Immunol187 (10): 5440–51. doi:10.4049/jimmunol.1100790. PMID22003197.
^Hook VY, Kindy M, Hook G (2008). "Inhibitors of cathepsin B improve memory and reduce Abeta in transgenic Alzheimer's Disease mice expressing the wild-type, but not the Swedish mutant, beta -secretase APP site". J Biol Chem283 (12): 7745–7753. doi:10.1074/jbc.m708362200. PMID18184658.
^Hook V, Kindy M, Hook G (2007). "Cysteine protease inhibitors effectively reduce in vivo levels of brain beta-amyloid related to Alzheimer's disease". Biol Chem388 (2): 247–52. doi:10.1515/bc.2007.027. PMID17261088.
^Hook G, Hook VY, Kindy M (2007). "Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer's disease therapeutics". Biol Chem388 (9): 979–83. doi:10.1515/BC.2007.117. PMID17696783.
^Hook VY, Kindy M, Reinheckel T, Peters C, Hook G (2009). "Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein". Biochem Biophys Res Commun386 (2): 284–8. doi:10.1016/j.bbrc.2009.05.131. PMID19501042.
^Hook G, Hook V, Kindy M (2011). "The Cysteine Protease Inhibitor, E64d, Reduces Brain Amyloid-beta and Improves Memory Deficits in Alzheimer's Disease Animal Models by Inhibiting Cathepsin B, but not BACE1, beta-Secretase Activity". J Alzheimers Dis26 (2): 387–408. doi:10.3233/JAD-2011-110101. PMID21613740.
^Kindy MS, Yu J, Zhu H, El-Amouri SS, Hook V, Hook GR (2012). "Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic Alzheimer's Disease Mouse Model Expressing AbetaPP Containing the Wild-Type beta-Secretase Site Sequence". J Alzheimers Dis29 (4): 827–40. doi:10.3233/JAD-2012-111604. PMID22337825.
^Hook G, Yu J, Toneff T, Kindy M, Hook V (2014). "Brain pyroglutamate amyloid-beta is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic". J Alzheimers Dis41 (1): 129–49. doi:10.3233/JAD-131370. PMID24595198.
^Hook V, Toneff T, Bogyo M, Greenbaum D, Medzihradszky KF, Neveu J, Lane W, Hook G, Reisine T (2005). "Inhibition of cathepsin B reduces β-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate β-secretase of Alzheimer's disease". Biological Chemistry386 (9): 931–940. doi:10.1515/BC.2005.108. PMID16164418.
^Klein DM, Felsenstein KM, Brenneman DE (2009). "Cathepsins B and L differentially regulate amyloid precursor protein processing". J Pharmacol Exp Ther329 (3): 813–21. doi:10.1124/jpet.108.147082. PMID19064719.
^ abPavlova A, Björk I (September 2003). "Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases". Biochemistry42 (38): 11326–33. doi:10.1021/bi030119v. PMID14503883.
^Estrada S, Nycander M, Hill NJ, Craven CJ, Waltho JP, Björk I (May 1998). "The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L". Biochemistry37 (20): 7551–60. doi:10.1021/bi980026r. PMID9585570.
^Mai J, Finley RL, Waisman DM, Sloane BF (April 2000). "Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells". J. Biol. Chem.275 (17): 12806–12. doi:10.1074/jbc.275.17.12806. PMID10777578.