en Neurophysiology/Pharmacology Neurophysiology/Pharmacology Experimental research article Experimental research article <div style="text-align: justify;"><strong><span class="fontstyle0">Introduction: </span></strong><span class="fontstyle2">Alzheimer&rsquo;s disease (AD) is a progressive and chronic neurodegenerative disorder in which amyloid-&beta; (A&beta;) 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 A&beta;-induced neurotoxicity in the </span><span class="fontstyle3">in-vivo </span><span class="fontstyle2">rat model.<strong> </strong></span><span class="fontstyle0"><strong>Methods:</strong> </span><span class="fontstyle2">Adult male Wistar rats were cannulated in the dorsal hippocampus and A&beta;</span><span class="fontstyle2" style="font-size:6pt;">25-35 </span><span class="fontstyle2">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. </span><span class="fontstyle0"><strong>Results:</strong> </span><span class="fontstyle2">Behavioral analysis showed that CEPO-Fc treatment significantly improved A&beta;-induced learning and memory impairment. Furthermore, the hippocampus&rsquo;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. </span><span class="fontstyle0"><strong>Conclusion:</strong> </span><span class="fontstyle2">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.</span></div> Alzheimer's disease, CEPO-Fc, Apoptosis, Autophagy, Necroptosis 272 287 http://ppj.phypha.ir/browse.php?a_code=A-10-1604-1&slc_lang=en&sid=1 Amirhossein Maghsoudi 3200319475328460031298 3200319475328460031298 No Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran Jalal Zaringhalam jzaringhalam@sbmu.ac.ir 3200319475328460031299 3200319475328460031299 Yes Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Maryam Moosavi 3200319475328460031300 3200319475328460031300 No Nanomedicine and Nanobiology Research Centre, Shiraz University of Medical sciences, Shiraz, Iran Akram Eidi 3200319475328460031301 3200319475328460031301 No Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran