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

Elevated A beta and its deposition as senile plaques are pathogenic features of Alzheimer's disease. A beta 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 A beta(1-42) increased Akt phosphorylation in an alpha(7) 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 (TAS 10) 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 A beta(1-42) regulates Akt phosphorylation in a complex manner. Acutely, A beta(1-42) stimulates Akt phosphorylation however, chronic exposure to A beta in TAS 10 mice resulted in a downregulation of Akt phosphorylation consistent with abnormalities in excitatory neurotransmission in these mice and with recent reports of A beta(1-42) driven internalisation of NMDA receptors. (C) 2007 Elsevier Inc. All rights reserved.