Memory Improvement in the AβPP/PS1 Mouse Model of Familial Alzheimer's Disease Induced by Carbamylated-Erythropoietin is Accompanied by Modulation of Synaptic Genes
Affiliations: [a] Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain | [b] CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Spain | [c] Departament de Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain | [d] Departament d'Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain | [e] Unitat d'Estadistica i Bioinformàtica, Institut de Recerca de l'Hospital Universitari de Vall d'Hebron, Barcelona, Spain
Correspondence:
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Correspondence to: Mercedes Armand-Ugón, Institut de Neuropatologia-IDIBELL, Universitat de Barcelona, Pavelló de Goven 4a, 4141, C/Feixa Llarga s/n, 08907–L'Hospitalet de Llobregat, Spain. Tel.: +34 934039994; Fax: +34 932607503; E-mail: [email protected].
Abstract: Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AβPP/PS1 mouse model of familial Alzheimer's disease. Groups of 5-month-old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 UI/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative-PCR were used for gene expression studies. No alterations in erythropoiesis were observed in CEPO-treated WT and AβPP/PS1 transgenic mice. EPO and CEPO improved memory in AβPP/PS1 animals. However, only EPO decreased amyloid-β (Aβ) plaque burden and soluble Aβ40. Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor α1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AβPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AβPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission.
