Abeta(1-42) modulation of Akt phosphorylation via alpha7 nAChR and NMDA receptors.
Elevated Abeta and its deposition as senile plaques are pathogenic features of Alzheimer's disease. Abeta 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 400nM Abeta(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 (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 Abeta(1-42) regulates Akt phosphorylation in a complex manner. Acutely, Abeta(1-42) stimulates Akt phosphorylation however, chronic exposure to Abeta in TAS10 mice resulted in a downregulation of Akt phosphorylation consistent with abnormalities in excitatory neurotransmission in these mice and with recent reports of Abeta(1-42) driven internalisation of NMDA receptors.
Abbott
Jonathan J
JJ
King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, St Thomas' Street, London SE1 1UL, UK.
Howlett
David R
DR
Francis
Paul T
PT
Williams
Robert J
RJ
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; C579166:Chrna7 protein, mouse; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D051057:Proto-Oncogene Proteins c-akt