carbamylated erythropoietin-fc ameliorates aβ25- 35 induced neurotoxicity by modulating autophagy, apoptosis and necroptosis in alzheimer’s disease model rats

Introduction: alzheimer’s disease (ad) is a progressive and chronic neurodegenerative disorder in which amyloid-β (aβ) and hyperphosphorylated-tau (p-tau) are well-established pathological hallmarks. carbamylated erythropoietin (cepo-fc) is one of the erythropoietin derivatives with neuroprotective properties against neurodegenerative disorders. however, the underlying molecular mechanism of cepo-fc has not been fully elucidated. therefore, we investigated the therapeutic effects of cepo-fc on aβ-induced neurotoxicity in the in-vivo rat model. methods: adult male wistar rats were cannulated in the dorsal hippocampus and aβ25-35 was microinjected for four consecutive days. cepo-fc was administered intranasally during the next six consecutive days. learning and memory performance were examined (days 10-13) using the morris water maze test. furthermore, the hippocampal levels of critical proteins involved in apoptosis (bax, bcl-2 and caspase-3), necroptosis (phosphorylatedreceptor-interacting serine/threonine-protein kinase 3) and autophagy (p-beclinbeclin-1 and phosphorylated- 1a/1b-light chain 3) were assessed using immunoblotting. results: behavioral analysis showed that cepo-fc treatment significantly improved aβ-induced learning and memory impairment. furthermore, the hippocampus’s molecular analysis showed that cepo-fc induced up-regulation of the autophagic proteins, p-beclin-1 and p-lc3-ii, while decreased caspase-3, bax/bcl2 ratio as well as the necroptosis factor p-rip3. conclusion: our results indicate that the neuroprotective properties of cepo-fc in animal model of ad could be mediated by autophagy activation and inhibition of apoptosis and necroptosis processes. this study introduces cepo-fc as a potential protective compound against ad and other neurodegenerative disorders.