An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease.
Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.
Department of Histology, Institute of Preclinical and Basic Sciences, University of Medical Sciences, Havana, Cuba.|Center of Molecular Immunology (CIM), Havana, Cuba.
Yamila
Y
Rodríguez Cruz
Inserm U1198, Montpellier, France.|University of Montpellier, Montpellier, France.|EPHE, Paris, France.
Manon
M
Strehaiano
Center of Molecular Immunology (CIM), Havana, Cuba.
Teresita
T
Rodríguez Obaya
Department of Histology, Institute of Preclinical and Basic Sciences, University of Medical Sciences, Havana, Cuba.
Julío César
JC
García Rodríguez
Inserm U1198, Montpellier, France.|University of Montpellier, Montpellier, France.|EPHE, Paris, France.
Tangui
T
Maurice
D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage* / Q000737:chemistry; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000737:chemistry
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D004921:Erythropoietin; D019158:N-Acetylneuraminic Acid
Alzheimer’s disease; Neuro-EPO; erythropoietin; intranasal formulation; learning and memory; neuroprotection