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؋APP transgenic mouse displaying early hippocampal A deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble A oligomers. We hypothesized that PI3K/Akt/GSK-3 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 was increased in the 6-month PS1؋APP hippocampus, whereas in aged PS1؋APP animals (18 months), GSK-3 phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-␣ (sAPP␣), the predominant APP-derived fragment in young PS1؋APP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3 activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric A forms, present in the soluble fractions of aged PS1؋APP mice, inhibited the induced phosphorylation of Akt/GSK-3 and decreased the neuronal survival. Furthermore, synthetic A oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPP␣, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3 signaling pathway through the major neurotrophin receptors. sAPP␣ stimulated and A oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.The molecular mechanisms underlying the selective neurodegeneration in Alzheimer disease (AD) 5 remain unclear. Amyloid- (A) peptides, proteolytically excised from the amyloid precursor protein (APP), are considered the primary pathological agents in AD. However, their precise modes of action, toxic conformational forms, and molecular targets are still controversial (for review see Ref. 1). Transgenic mouse models, overexpressing mutated forms of human APP, are widely used to study AD pathogenesis. These models develop extensive A deposition in the disease-vulnerable brain regions (such as hippocampus); however, neurons are well protected until late ages. The factors and pathways maintaining neuronal integrity at young/middle ages in these AD models and those inducing neurodegeneration in the aged animals remains to be defined.NGF, BDNF, IGF-1, and insulin are trophic factors critical for neuronal survival and plasticity, underlying memory, and learning (2-4) and could be implicated in AD development.
