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An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease.
J Alzheimers Dis. 2017; 55(1):231-248.JA

Abstract

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.

Authors+Show Affiliations

Department of Histology, Institute of Preclinical and Basic Sciences, University of Medical Sciences, Havana, Cuba. Center of Molecular Immunology (CIM), Havana, Cuba.Inserm U1198, Montpellier, France. University of Montpellier, Montpellier, France. EPHE, Paris, France.Center of Molecular Immunology (CIM), Havana, Cuba.Department of Histology, Institute of Preclinical and Basic Sciences, University of Medical Sciences, Havana, Cuba.Inserm U1198, Montpellier, France. University of Montpellier, Montpellier, France. EPHE, Paris, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27662300

Citation

Rodríguez Cruz, Yamila, et al. "An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease." Journal of Alzheimer's Disease : JAD, vol. 55, no. 1, 2017, pp. 231-248.
Rodríguez Cruz Y, Strehaiano M, Rodríguez Obaya T, et al. An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2017;55(1):231-248.
Rodríguez Cruz, Y., Strehaiano, M., Rodríguez Obaya, T., García Rodríguez, J. C., & Maurice, T. (2017). An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease : JAD, 55(1), 231-248.
Rodríguez Cruz Y, et al. An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2017;55(1):231-248. PubMed PMID: 27662300.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease. AU - Rodríguez Cruz,Yamila, AU - Strehaiano,Manon, AU - Rodríguez Obaya,Teresita, AU - García Rodríguez,Julío César, AU - Maurice,Tangui, PY - 2016/9/24/pubmed PY - 2018/2/16/medline PY - 2016/9/24/entrez KW - Alzheimer’s disease KW - Neuro-EPO KW - erythropoietin KW - intranasal formulation KW - learning and memory KW - neuroprotection SP - 231 EP - 248 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 55 IS - 1 N2 - 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. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/27662300/An_Intranasal_Formulation_of_Erythropoietin__Neuro_EPO__Prevents_Memory_Deficits_and_Amyloid_Toxicity_in_the_APPSwe_Transgenic_Mouse_Model_of_Alzheimer's_Disease_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-160500 DB - PRIME DP - Unbound Medicine ER -