Aβ1–42 modulation of Akt phosphorylation via α7 nAChR and NMDA receptors

Elevated Aβ and its deposition as senile plaques are pathogenic features of Alzheimerʹs disease. Aβ has been shown to be toxic to neurons and to inhibit long-term potentiation yet, the intracellular signalling pathways underlying these actions are unknown. We report for the first time that acute exposure of primary mouse neurons to 400 nM Aβ1–42 increased Akt phosphorylation in an α7 nicotinic receptor and NMDA receptor dependant manner. However, prolonged incubation resulted in Akt phosphorylation returning to baseline consistent with the action of a physiological regulator. Analysis of an APP transgenic mouse (TAS10) revealed a significant deficit in hippocampal Akt phosphorylation at 13 months. This time point corresponds to the emergence of plaque formation and memory impairments in these mice. The present study suggests that Aβ1–42 regulates Akt phosphorylation in a complex manner. Acutely, Aβ1–42 stimulates Akt phosphorylation however, chronic exposure to Aβ in TAS10 mice resulted in a downregulation of Akt phosphorylation consistent with abnormalities in excitatory neurotransmission in these mice and with recent reports of Aβ1–42 driven internalisation of NMDA receptors.