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Abstract:   (450 Views)
Introduction: Alzheimer’s disease (AD) is marked by the deposition of amyloid-β (Aβ) plaques and tau tangles. Although Erythropoietin (EPO) provides neuroprotective and memory-improving properties, its application has been limited due to the hematopoietic effects. Carbamylated Erythropoietin-Fc (CEPO-Fc) was developed as a non-erythropoietic EPO derivative that possesses neuroprotective potential. However, the molecular mechanisms behind the protective effects of CEPO-Fc's in AD are still under consideration. Therefore, herein investigated the therapeutic properties of intraperitoneal (i.p.) dose of CEPO-Fc on Aβ-induced neurotoxicity in adult male Wistar rats.
Methods: The rats received microinjections of Aβ25-35 (5 μg/2.5 μl, per side) in the dorsal hippocampus for four consecutive days. CEPO-Fc was injected intraperitoneally in two doses of 500 and 5000 IU during the next six days. Learning and memory performance were studied (days 10-13) using the Morris Water Maze task. Immunoblotting was also undertaken to assess the molecular levels of leading indicators of apoptosis (Bax, Bcl-2, and caspase-3), necroptosis (Phosphorylated-Receptor-interacting serine/threonine-protein kinase 3 (p-RIP3)), as well as autophagy (phosphorylated-Beclin-1 (p-Beclin-1) and phosphorylated-1A/1B-light chain 3 (p-LC3-II)) in the hippocampus.
Results: Behavioral analysis indicated that CEPO-Fc 500 and 5000 IU reversed memory impairment. Moreover, the hippocampus's molecular study showed upregulation of P-LC3-II/LC3-II and suppression of Bax/Bcl-2, Caspase-3, and P-RIP3/RIP3 processes.
Conclusion: Our findings imply that the neuroprotective characteristics of CEPO-Fc in the AD rats are mediated through autophagy activation and regulation of apoptosis and necroptosis processes. These results suggest that an i.p. dose of CEPO-Fc could be used to protect against AD-induced neurotoxicity.

1. Adembri, C., Massagrande, A., Tani, A., Miranda, M., Margheri, M., De Gaudio, R., & Pellegrini-Giampietro, D. E. (2008). Carbamylated erythropoietin is neuroprotective in an experimental model of traumatic brain injury. Critical care medicine, 36(3), 975-978. [DOI:10.1097/CCM.0B013E3181644343]
2. Bernard, A., & Klionsky, D. J. (2014). Defining the membrane precursor supporting the nucleation of the phagophore. In: Taylor & Francis. [DOI:10.4161/auto.27242]
3. Bloom, G. S. (2014). Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology, 71(4), 505-508. [DOI:10.1001/jamaneurol.2013.5847]
4. Boland, B., Kumar, A., Lee, S., Platt, F. M., Wegiel, J., Yu, W. H., & Nixon, R. A. (2008). Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. Journal of Neuroscience, 28(27), 6926-6937. [DOI:10.1523/JNEUROSCI.0800-08.2008]
5. Caccamo, A., Branca, C., Piras, I. S., Ferreira, E., Huentelman, M. J., Liang, W. S., Readhead, B., Dudley, J. T., Spangenberg, E. E., & Green, K. N. (2017). Necroptosis activation in Alzheimer's disease. Nature Neuroscience, 20(9), 1236. [DOI:10.1038/nn.4608]
6. Calvo-Rodriguez, M., Hou, S. S., Snyder, A. C., Kharitonova, E. K., Russ, A. N., Das, S., Fan, Z., Muzikansky, A., Garcia-Alloza, M., & Serrano-Pozo, A. (2020). Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease. Nature communications, 11(1), 1-17. [DOI:10.1038/s41467-020-16074-2]
7. Castañeda-Arellano, R., Feria-Velasco, A., & Rivera-Cervantes, M. (2014). Activity increase in EpoR and Epo expression by intranasal recombinant human erythropoietin (rhEpo) administration in ischemic hippocampi of adult rats. Neuroscience letters, 583, 16-20. [DOI:10.1016/j.neulet.2014.09.013]
8. Cataldo, A. M., Peterhoff, C. M., Schmidt, S. D., Terio, N. B., Duff, K., Beard, M., Mathews, P. M., & Nixon, R. A. (2004). Presenilin mutations in familial Alzheimer's disease and transgenic mouse models accelerate neuronal lysosomal pathology. Journal of neuropathology & experimental neurology, 63(8), 821-830. [DOI:10.1093/jnen/63.8.821]
9. Chamorro, M. E., Maltaneri, R. E., Vittori, D. C., & Nesse, A. B. (2015). Protein tyrosine phosphatase 1B (PTP1B) is involved in the impaired erythropoietic function of carbamylated erythropoietin. Int J Biochem Cell Biol, 61, 63-71. [DOI:10.1016/j.biocel.2015.01.019]
10. Chamorro, M. E., Wenker, S. D., Vota, D. M., Vittori, D. C., & Nesse, A. B. (2013). Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1833(8), 1960-1968. [DOI:10.1016/j.bbamcr.2013.04.006]
11. Chen, J., Yang, Z., & Zhang, X. (2015). Carbamylated Erythropoietin: A Prospective Drug Candidate for Neuroprotection. Biochem Insights, 8(Suppl 1), 25-29. [DOI:10.4137/bci.S30753]
12. Choi, M., Ko, S. Y., Lee, I. Y., Wang, S. E., Lee, S. H., Oh, D. H., Kim, Y.-S., & Son, H. (2014). Carbamylated erythropoietin promotes neurite outgrowth and neuronal spine formation in association with CBP/p300. Biochemical and biophysical research communications, 446(1), 79-84. [DOI:10.1016/j.bbrc.2014.02.066]
13. Choi, M., Ko, S. Y., Lee, I. Y., Wang, S. E., Lee, S. H., Oh, D. H., Kim, Y. S., & Son, H. (2014). Carbamylated erythropoietin promotes neurite outgrowth and neuronal spine formation in association with CBP/p300. Biochem Biophys Res Commun, 446(1), 79-84. [DOI:10.1016/j.bbrc.2014.02.066]
14. Derk, J., MacLean, M., Juranek, J., & Schmidt, A. M. (2018). The receptor for advanced glycation endproducts (RAGE) and mediation of inflammatory neurodegeneration. Journal of Alzheimer's disease & Parkinsonism, 8(1). [DOI:10.4172/2161-0460.1000421]
15. Fan, T.-J., Han, L.-H., Cong, R.-S., & Liang, J. (2005). Caspase family proteases and apoptosis. Acta Biochimica et Biophysica Sinica, 37(11), 719-727. [DOI:10.1111/j.1745-7270.2005.00108.x]
16. Fantacci, M., Bianciardi, P., Caretti, A., Coleman, T. R., Cerami, A., Brines, M., & Samaja, M. (2006). Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia. Proceedings of the National Academy of Sciences, 103(46), 17531-17536. [DOI:10.1073/pnas.0608814103]
17. Frick, K. M., Kim, J., Tuscher, J. J., & Fortress, A. M. (2015). Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents. Learning & Memory, 22(9), 472-493. [DOI:10.1101/lm.037267.114]
18. Genc, S., Zadeoglulari, Z., Oner, M. G., Genc, K., & Digicaylioglu, M. (2011). Intranasal erythropoietin therapy in nervous system disorders. Expert opinion on drug delivery, 8(1), 19-32. [DOI:10.1517/17425247.2011.540236]
19. Guzy, R. (2005). Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab, 1, 401-408. [DOI:10.1016/j.cmet.2005.05.001]
20. Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., & Okano, H. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 441(7095), 885-889. [DOI:10.1038/nature04724]
21. Harris, H., & Rubinsztein, D. C. (2012). Control of autophagy as a therapy for neurodegenerative disease. Nature Reviews Neurology, 8(2), 108-117. [DOI:10.1038/nrneurol.2011.200]
22. Hooshmandi, E., Moosavi, M., Katinger, H., Sardab, S., Ghasemi, R., & Maghsoudi, N. (2020). CEPO (carbamylated erythropoietin)-Fc protects hippocampal cells in culture against beta-amyloid-induced apoptosis: considering Akt/GSK-3β and ERK signaling pathways. Molecular biology reports, 47(3), 2097-2108. [DOI:10.1007/s11033-020-05309-6]
23. Hooshmandi, E., Motamedi, F., Moosavi, M., Katinger, H., Zakeri, Z., Zaringhalam, J., Maghsoudi, A., Ghasemi, R., & Maghsoudi, N. (2018). CEPO-Fc (an EPO derivative) protects hippocampus against Aβ-induced memory deterioration: a behavioral and molecular study in a rat model of Aβ toxicity. Neuroscience, 388, 405-417. [DOI:10.1016/j.neuroscience.2018.08.001]
24. Hu, L., Zhang, R., Yuan, Q., Gao, Y., Yang, M. Q., Zhang, C., Huang, J., Sun, Y., Yang, W., & Yang, J. Y. (2018). The emerging role of microRNA-4487/6845-3p in Alzheimer's disease pathologies is induced by Aβ25-35 triggered in SH-SY5Y cell. BMC systems biology, 12(7), 1-10. [DOI:10.1186/s12918-018-0633-3]
25. Hwang, C. H. (2020). Targeted Delivery of Erythropoietin Hybridized with Magnetic Nanocarriers for the Treatment of Central Nervous System Injury: A Literature Review. International Journal of Nanomedicine, 15, 9683. [DOI:10.2147/IJN.S287456]
26. Kim, H. Y., Moon, C., Kim, K. S., Oh, K. W., Oh, S.-i., Kim, J., & Kim, S. H. (2014). Recombinant human erythropoietin in amyotrophic lateral sclerosis: a pilot study of safety and feasibility. Journal of clinical neurology, 10(4), 342-347. [DOI:10.3988/jcn.2014.10.4.342]
27. King, V., Averill, S., Hewazy, D., Priestley, J., Torup, L., & Michael‐Titus, A. (2007). Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord hemisection in the rat. European Journal of Neuroscience, 26(1), 90-100. [DOI:10.1111/j.1460-9568.2007.05635.x]
28. Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.-i., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., & Kominami, E. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 441(7095), 880-884. [DOI:10.1038/nature04723]
29. Kuang, H., Tan, C. Y., Tian, H. Z., Liu, L. H., Yang, M. W., Hong, F. F., & Yang, S. L. (2020). Exploring the bi‐directional relationship between autophagy and Alzheimer's disease. CNS neuroscience & therapeutics, 26(2), 155-166. [DOI:10.1111/cns.13216]
30. Larpthaveesarp, A., Pathipati, P., Ostrin, S., Rajah, A., Ferriero, D., & Gonzalez, F. F. (2021). Enhanced Mesenchymal Stromal Cells or Erythropoietin Provide Long-Term Functional Benefit After Neonatal Stroke. Stroke, 52(1), 284-293. [DOI:10.1161/STROKEAHA.120.031191]
31. Lauria, G., Dalla Bella, E., Antonini, G., Borghero, G., Capasso, M., Caponnetto, C., Chiò, A., Corbo, M., Eleopra, R., & Fazio, R. (2015). Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomized, double-blind, placebo-controlled, phase III study. Journal of Neurology, Neurosurgery & Psychiatry, 86(8), 879-886. [DOI:10.1136/jnnp-2014-308996]
32. Leyland-Jones, B. (2003). Breast cancer trial with erythropoietin terminated unexpectedly. The Lancet. Oncology, 4(8), 459-460. [DOI:10.1016/S1470-2045(03)01163-X]
33. Li, J., McQuade, T., Siemer, A. B., Napetschnig, J., Moriwaki, K., Hsiao, Y.-S., Damko, E., Moquin, D., Walz, T., & McDermott, A. (2012). The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell, 150(2), 339-350. [DOI:10.1016/j.cell.2012.06.019]
34. Li, Y., Yang, X., Ma, C., Qiao, J., & Zhang, C. (2008). Necroptosis contributes to the NMDA-induced excitotoxicity in rat's cultured cortical neurons. Neuroscience Letters, 447(2-3), 120-123. [DOI:10.1016/j.neulet.2008.08.037]
35. Liao, Z., Zhi, X., Shi, Q., & He, Z. (2008). Recombinant human erythropoietin administration protects cortical neurons from traumatic brain injury in rats. European journal of neurology, 15(2), 140-149. [DOI:10.1111/j.1468-1331.2007.02013.x]
36. Lipinski, M. M., Zheng, B., Lu, T., Yan, Z., Py, B. F., Ng, A., Xavier, R. J., Li, C., Yankner, B. A., & Scherzer, C. R. (2010). Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and Alzheimer's disease. Proceedings of the National Academy of Sciences, 107(32), 14164-14169. [DOI:10.1073/pnas.1009485107]
37. Liu, J., & Li, L. (2019). Targeting autophagy for the treatment of Alzheimer's disease: challenges and opportunities. Frontiers in molecular neuroscience, 12, 203. [DOI:10.3389/fnmol.2019.00203]
38. Liu, M., Wang, A. J., Chen, Y., Zhao, G., Jiang, Z., Wang, X., Shi, D., Zhang, T., Sun, B., & He, H. (2020). Efficacy and safety of erythropoietin for traumatic brain injury. BMC neurology, 20(1), 1-13. [DOI:10.1186/s12883-020-01958-z]
39. Liu, Z., Zhang, B., Xia, S., Fang, L., & Gou, S. (2021). ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker. European journal of medicinal chemistry, 212, 112997. [DOI:10.1016/j.ejmech.2020.112997]
40. Lu, S., Wei, X., Zhang, H., Chen, Z., Li, J., Xu, X., Xie, Q., Chen, L., Ye, F., & Phama, H. T. T. (2021). Protective effect of 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione, isolated from Averrhoa carambola L., against Aβ1-42-induced apoptosis in SH-SY5Y cells by reversing Bcl-2/Bax ratio. Psychopharmacology, 238(1), 193-200. [DOI:10.1007/s00213-020-05668-9]
41. Luo, Y., Zhou, S., Haeiwa, H., Takeda, R., Okazaki, K., Sekita, M., Yamamoto, T., Yamano, M., & Sakamoto, K. (2021). Role of amber extract in protecting SHSY5Y cells against amyloid β1-42-induced neurotoxicity. Biomedicine & Pharmacotherapy, 141, 111804. [DOI:10.1016/j.biopha.2021.111804]
42. Ma, B.-X., Li, J., Li, H., & Wu, S.-S. (2015). Recombinant human erythropoietin protects myocardial cells from apoptosis via the Janus-activated kinase 2/signal transducer and activator of transcription five pathway in rats with epilepsy. Current Therapeutic Research, 77, 90-98. [DOI:10.1016/j.curtheres.2015.07.001]
43. Macias-Velez, R., de León, L. F.-D., Beas-Zárate, C., & Rivera-Cervantes, M. (2019). Intranasal erythropoietin protects ca1 hippocampal cells, modulated by specific time pattern molecular changes after ischemic damage in rats. Journal of Molecular Neuroscience, 68(4), 590-602. [DOI:10.1007/s12031-019-01308-w]
44. Mahmood, A., Lu, D., Qu, C., Goussev, A., Zhang, Z. G., Lu, C., & Chopp, M. (2007). Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. Journal of neurosurgery, 107(2), 392-397. [DOI:10.3171/JNS-07/08/0392]
45. Maltaneri, R. E., Chamorro, M. E., Schiappacasse, A., Nesse, A. B., & Vittori, D. C. (2017). Differential effect of erythropoietin and carbamylated erythropoietin on endothelial cell migration. The international journal of biochemistry & cell biology, 85, 25-34. [DOI:10.1016/j.biocel.2017.01.013]
46. Maurice, T., Mustafa, M. H., Desrumaux, C., Keller, E., Naert, G., de la, C. G.-B. M., Rodríguez Cruz, Y., & Garcia Rodríguez, J. C. (2013). Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ₂₅₋₃₅ non-transgenic mouse model of Alzheimer's disease. J Psychopharmacol, 27(11), 1044-1057. [DOI:10.1177/0269881113494939]
47. Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010). Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science, 330(6012), 1774-1774. [DOI:10.1126/science.1197623]
48. Mennini, T., De Paola, M., Bigini, P., Mastrotto, C., Fumagalli, E., Barbera, S., Mengozzi, M., Viviani, B., Corsini, E., & Marinovich, M. (2006). Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo. Molecular medicine, 12(7), 153-160. [DOI:10.2119/2006-00045.Mennini]
49. Metaxakis, A., Ploumi, C., & Tavernarakis, N. (2018). Autophagy in age-associated neurodegeneration. Cells, 7(5), 37. [DOI:10.3390/cells7050037]
50. Mohamed, T., Shakeri, A., & Rao, P. P. (2016). Amyloid cascade in Alzheimer's disease: recent advances in medicinal chemistry. European journal of medicinal chemistry, 113, 258-272. [DOI:10.1016/j.ejmech.2016.02.049]
51. Moon, C., Krawczyk, M., Paik, D., Coleman, T., Brines, M., Juhaszova, M., Sollott, S. J., Lakatta, E. G., & Talan, M. I. (2006). Erythropoietin, modified not to stimulate red blood cell production, retains its cardioprotective properties. Journal of Pharmacology and Experimental Therapeutics, 316(3), 999-1005. [DOI:10.1124/jpet.105.094854]
52. Moosavi, M., Hooshmandi, E., Javadpour, P., Maghsoudi, N., Katinger, H., & Ghasemi, R. (2020). Effect of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) on learning and memory impairment and hippocampal apoptosis induced by intracerebroventricular administration of streptozotocin in rats. Behavioral brain research, 384, 112554. [DOI:10.1016/j.bbr.2020.112554]
53. Moransard, M., Bednar, M., Frei, K., Gassmann, M., & Ogunshola, O. (2017). Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms. Journal of neuroinflammation, 14(1), 1-13. [DOI:10.1186/s12974-017-0976-5]
54. Nilsson, P., & Saido, T. C. (2014). Dual roles for autophagy: degradation and secretion of Alzheimer's disease Aβ peptide. Bioessays, 36(6), 570-578. [DOI:10.1002/bies.201400002]
55. Ofengeim, D., Ito, Y., Najafov, A., Zhang, Y., Shan, B., DeWitt, J. P., Ye, J., Zhang, X., Chang, A., & Vakifahmetoglu-Norberg, H. (2015). Activation of necroptosis in multiple sclerosis. Cell reports, 10(11), 1836-1849. [DOI:10.1016/j.celrep.2015.02.051]
56. Paxinos, G., & Watson, C. (2007). The rat brain in stereotaxic coordinates. Amsterdam. In: Boston: Academic Press/Elsevier.
57. Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B., Rockenstein, E., & Levine, B. (2008). The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer's disease and regulates amyloid β accumulation in mice. The Journal of clinical investigation, 118(6), 2190-2199. [DOI:10.1172/JCI33585]
58. Pourhamzeh, M., Joghataei, M. T., Mehrabi, S., Ahadi, R., Hojjati, S. M. M., Fazli, N., Nabavi, S. M., Pakdaman, H., & Shahpasand, K. (2020). The Interplay of Tau Protein and β-Amyloid: While Tauopathy Spreads More Profoundly Than Amyloidopathy, Both Processes Are Almost Equally Pathogenic. Cellular and Molecular Neurobiology, 1-16. [DOI:10.1007/s10571-020-00906-2]
59. Rahman, M., Rahman, M. S., Rahman, M., Rasheduzzaman, M., Mamun-Or-Rashid, A., Uddin, M. J., Rahman, M. R., Hwang, H., Pang, M.-G., & Rhim, H. (2021). Modulatory Effects of Autophagy on APP Processing as a Potential Treatment Target for Alzheimer's Disease. Biomedicines, 9(1), 5. [DOI:10.3390/biomedicines9010005]
60. Rocchi, A., Yamamoto, S., Ting, T., Fan, Y., Sadleir, K., Wang, Y., Zhang, W., Huang, S., Levine, B., & Vassar, R. (2017). A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease. PLoS genetics, 13(8), e1006962. [DOI:10.1371/journal.pgen.1006962]
61. Rohn, T. T., Wirawan, E., Brown, R. J., Harris, J. R., Masliah, E., & Vandenabeele, P. (2011). Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer's disease brain. Neurobiology of Disease, 43(1), 68-78. [DOI:10.1016/j.nbd.2010.11.003]
62. Sathyanesan, M., Watt, M. J., Haiar, J. M., Scholl, J. L., Davies, S. R., Paulsen, R. T., Wiederin, J., Ciborowski, P., & Newton, S. S. (2018). Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus. Translational psychiatry, 8(1), 1-13. [DOI:10.1038/s41398-018-0168-9]
63. Schriebl, K., Trummer, E., Lattenmayer, C., Weik, R., Kunert, R., Mueller, D., Katinger, H., & Vorauer-Uhl, K. (2006). Biochemical characterization of rhEpo-Fc fusion protein expressed in CHO cells. Protein expression and purification, 49(2), 265-275. [DOI:10.1016/j.pep.2006.05.018]
64. Skrifvars, M. B., Bailey, M., French, C., Presneill, J., Nichol, A., Little, L., Duranteau, J., Huet, O., Haddad, S., & Arabi, Y. (2017). Erythropoietin in patients with traumatic brain injury and extracranial injury-A post hoc analysis of the erythropoietin traumatic brain injury trial. Journal of Trauma and Acute Care Surgery, 83(3), 449-456. [DOI:10.1097/TA.0000000000001594]
65. Subramanian, M., Hyeon, S. J., Das, T., Suh, Y. S., Kim, Y. K., Lee, J.-S., Song, E. J., Ryu, H., & Yu, K. (2021). UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation. Nature communications, 12(1), 1-15. [DOI:10.1038/s41467-021-23597-9]
66. Sun, J., Martin, J. M., Vanderpoel, V., & Sumbria, R. K. (2019). The promises and challenges of erythropoietin for treatment of Alzheimer's disease. Neuromolecular medicine, 21(1), 12-24. [DOI:10.1007/s12017-019-08524-y]
67. Swaminathan, G., Zhu, W., & Plowey, E. D. (2016). BECN1/Beclin 1 sorts cell-surface APP/amyloid β precursor protein for lysosomal degradation. Autophagy, 12(12), 2404-2419. [DOI:10.1080/15548627.2016.1234561]
68. Thomas Tayra, J., Kameda, M., Yasuhara, T., Agari, T., Kadota, T., Wang, F., Kikuchi, Y., Liang, H., Shinko, A., Wakamori, T., Vcelar, B., Weik, R., & Date, I. (2013). The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease. Brain Res, 1502, 55-70. [DOI:10.1016/j.brainres.2013.01.042]
69. Tiwari, N. K., Sathyanesan, M., Schweinle, W., & Newton, S. S. (2019). Carbamoylated erythropoietin induces a neurotrophic gene profile in neuronal cells. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 88, 132-141. [DOI:10.1016/j.pnpbp.2018.07.011]
70. Tóthová, Z., Šemeláková, M., Solárová, Z., Tomc, J., Debeljak, N., & Solár, P. (2021). The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization. Int J Mol Sci, 22(14). [DOI:10.3390/ijms22147682]
71. Wang, H., Ma, J., Tan, Y., Wang, Z., Sheng, C., Chen, S., & Ding, J. (2010). Amyloid-β 1-42 induces reactive oxygen species-mediated autophagic cell death in U87 and SH-SY5Y cells. Journal of Alzheimer's Disease, 21(2), 597-610. [DOI:10.3233/JAD-2010-091207]
72. Wang, Y., Zhang, Z., Rhodes, K., Renzi, M., Zhang, R., Kapke, A., Lu, M., Pool, C., Heavner, G., & Chopp, M. (2007). Post‐ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia. British journal of pharmacology, 151(8), 1377-1384. [DOI:10.1038/sj.bjp.0707285]
73. Wun, T., Law, L., Harvey, D., Sieracki, B., Scudder, S. A., & Ryu, J. K. (2003). Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer: Interdisciplinary International Journal of the American Cancer Society, 98(7), 1514-1520. [DOI:10.1002/cncr.11700]
74. Xilouri, M., & Stefanis, L. (2010). Autophagy in the central nervous system: implications for neurodegenerative disorders. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 9(6), 701-719. [DOI:10.2174/187152710793237421]
75. Xiong, Y., Mahmood, A., Zhang, Y., Meng, Y., Zhang, Z. G., Qu, C., Sager, T. N., & Chopp, M. (2011). Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis and improving functional outcome in rats following traumatic brain injury. Journal of neurosurgery, 114(2), 549-559. [DOI:10.3171/2010.10.JNS10925]
76. Xu, X., Cao, Z., Cao, B., Li, J., Guo, L., Que, L., Ha, T., Chen, Q., Li, C., & Li, Y. (2009). Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Surgery, 146(3), 506-514. [DOI:10.1016/j.surg.2009.03.022]
77. Xu, X., Chua, C. C., Kong, J., Kostrzewa, R. M., Kumaraguru, U., Hamdy, R. C., & Chua, B. H. (2007). Necrostatin‐1 protects against glutamate‐induced glutathione depletion and caspase‐independent cell death in HT‐22 cells. Journal of neurochemistry, 103(5), 2004-2014. [DOI:10.1111/j.1471-4159.2007.04884.x]
78. Yang, D.-S., Stavrides, P., Mohan, P. S., Kaushik, S., Kumar, A., Ohno, M., Schmidt, S. D., Wesson, D., Bandyopadhyay, U., & Jiang, Y. (2011). Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain, 134(1), 258-277. [DOI:10.1093/brain/awq341]
79. Yu, Y.-P., Xu, Q.-Q., Zhang, Q., Zhang, W.-P., Zhang, L.-H., & Wei, E.-Q. (2005). Intranasal recombinant human erythropoietin protects rats against focal cerebral ischemia. Neuroscience Letters, 387(1), 5-10. [DOI:10.1016/j.neulet.2005.07.008]
80. Yu, Y. P., Xu, Q. Q., Zhang, Q., Zhang, W. P., Zhang, L. H., & Wei, E. Q. (2005). Intranasal recombinant human erythropoietin protects rats against focal cerebral ischemia. Neurosci Lett, 387(1), 5-10. [DOI:10.1016/j.neulet.2005.07.008]
81. Yuan, J., Amin, P., & Ofengeim, D. (2019). Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nature Reviews Neuroscience, 20(1), 19-33. [DOI:10.1038/s41583-018-0093-1]
82. Zhang, J., Ding, Y.-r., & Wang, R. (2016). Inhibition of tissue transglutaminase promotes Aβ-induced apoptosis in SH-SY5Y cells. Acta Pharmacologica Sinica, 37(12), 1534-1542. [DOI:10.1038/aps.2016.95]
83. Zhang, S., Tang, M.-b., Luo, H.-y., Shi, C.-h., & Xu, Y.-m. (2017). Necroptosis in neurodegenerative diseases: a potential therapeutic target. Cell death & disease, 8(6), e2905-e2905. [DOI:10.1038/cddis.2017.286]
84. Zheng, L., Terman, A., Hallbeck, M., Dehvari, N., Cowburn, R. F., Benedikz, E., Kågedal, K., Cedazo-Minguez, A., & Marcusson, J. (2011). Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells. Autophagy, 7(12), 1528-1545. [DOI:10.4161/auto.7.12.18051]
85. Zhong, L., Zhang, H., Ding, Z.-F., Li, J., Lv, J.-W., Pan, Z.-J., Xu, D.-X., & Yin, Z.-S. (2020). Erythropoietin-induced autophagy protects against spinal cord injury and improves neurological function via the extracellular-regulated protein kinase signaling pathway. Molecular Neurobiology, 57(10), 3993-4006. [DOI:10.1007/s12035-020-01997-0]
86. Zhou, Y., Sun, B., Guo, J., & Zhou, G. (2020). Intranasal injection of recombinant human erythropoietin improves cognitive and visual impairments in chronic cerebral ischemia rats. Biomedical Reports, 13(5), 1-1. [DOI:10.3892/br.2020.1347]

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