An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APP_Swe Transgenic Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Rodríguez Cruz, Yamila^{a; b} | Strehaiano, Manon^{c; d; e} | Rodríguez Obaya, Teresita^b | García Rodríguez, Julío César^a | Maurice, Tangui^{c; d; e; *}

Affiliations: [a] Department of Histology, Institute of Preclinical and Basic Sciences, University of Medical Sciences, Havana, Cuba | [b] Center of Molecular Immunology (CIM), Havana, Cuba | [c] Inserm U1198, Montpellier, France | [d] University of Montpellier, Montpellier, France | [e] EPHE, Paris, France

Correspondence: [*] Correspondence to: Dr. Tangui Maurice, INSERM U1198, Université de Montpellier, CC105, place Eugène Bataillon, 34095 Montpellier cedex 5, France. Tel.: +33 0 4 67 14 36 23; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, erythropoietin, intranasal formulation, learning and memory, Neuro-EPO, neuroprotection

DOI: 10.3233/JAD-160500

Journal: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 231-248, 2017