Age-dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (sAPPα) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model

Neurotrophins, 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 PS1 x APP transgenic mouse displaying early hippocampal A beta deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble A beta oligomers. We hypothesized that PI3K/Akt/GSK-3 beta 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-3 beta was increased in the 6-month PS1 x APP hippocampus, whereas in aged PS1 x APP animals (18 months), GSK-3 beta phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-alpha (sAPP alpha), the predominant APP-derived fragment in young PS1 x APP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3 beta activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric A beta forms, present in the soluble fractions of aged PS1 x APP mice, inhibited the induced phosphorylation of Akt/GSK-3 beta and decreased the neuronal survival. Furthermore, synthetic A beta oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPP alpha, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3 beta signaling pathway through the major neurotrophin receptors. sAPP alpha stimulated and A beta oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.