1-42 modulation of Akt phosphorylation via α7 nAChR and NMDA receptors

Jonathan J Abbott, David R Howlett, Paul T Francis, Robert J Williams

Research output: Contribution to journalArticle

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Abstract

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.
LanguageEnglish
Pages992-1001
Number of pages10
JournalNeurobiology of Aging
Volume29
Issue number7
Early online date10 Feb 2007
DOIs
StatusPublished - Jul 2008

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N-Methyl-D-Aspartate Receptors
Phosphorylation
Neurons
Long-Term Potentiation
Poisons
Amyloid Plaques
Nicotinic Receptors
Synaptic Transmission
Transgenic Mice
amyloid beta-protein (1-42)
Alzheimer Disease
Down-Regulation

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1-42 modulation of Akt phosphorylation via α7 nAChR and NMDA receptors. / Abbott, Jonathan J; Howlett, David R; Francis, Paul T; Williams, Robert J.

In: Neurobiology of Aging, Vol. 29, No. 7, 07.2008, p. 992-1001.

Research output: Contribution to journalArticle

Abbott, Jonathan J ; Howlett, David R ; Francis, Paul T ; Williams, Robert J. / 1-42 modulation of Akt phosphorylation via α7 nAChR and NMDA receptors. In: Neurobiology of Aging. 2008 ; Vol. 29, No. 7. pp. 992-1001
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