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Age-dependent accumulation of soluble amyloid ß (Aß) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-α (sAPPα) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK- 3ß pathway in Alzheimer mouse model.

AuthorsJiménez, Sebastián; Torres, Manuel; Vizuete, Marisa; Carmona-Cuenca, Irene; Caballero, Cristina; Ruano, Diego; Vitorica, Javier
Issue Date2011
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 286(21): 18414-18425 (2011)
AbstractNeurotrophins, activating the PI3K/Akt signaling pathway, control neuronal survival and plasticity. Alterations in NGF, BDNF, IGF-1, or insulin signaling are implicated in the pathogenesis of Alzheimer disease. We have previously characterized a bigenic PS1xAPP transgenic mouse displaying early hippocampal Aß deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble Aß oligomers. We hypothesized that PI3K/Akt/GSK-3ß signaling pathway could be involved in this apparent age-dependent neuroprotective/neurodegenerative status. In fact, our data demonstrated that, as compared with age-matched nontransgenic controls, the Ser-9 phosphorylation of GSK-3ß was increased in the 6-month PS1xAPP hippocampus, whereas in aged PS1xAPP animals (18 months), GSK-3ß phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-α (sAPPα), the predominant APP-derived fragment in young PS1xAPP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3ß activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric Aß forms, present in the soluble fractions of aged PS1xAPP mice, inhibited the induced phosphorylation of Akt/GSK-3ß and decreased the neuronal survival. Furthermore, synthetic Aß oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPPα, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3ß signaling pathway through the major neurotrophin receptors. sAPPα stimulated and Aß oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.
Identifiersdoi: 10.1074/jbc.M110.209718
issn: 0021-9258
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