beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Judit EspañaCarlos A Saura

Abstract

Activity-dependent gene expression mediating changes of synaptic efficacy is important for memory storage, but the mechanisms underlying gene transcriptional changes in age-related memory disorders are poorly understood. In this study, we report that gene transcription mediated by the cAMP-response element binding protein (CREB)-regulated transcription coactivator CRTC1 is impaired in neurons and brain from an Alzheimer's disease (AD) transgenic mouse expressing the human beta-amyloid precursor protein (APP(Sw,Ind)). Suppression of CRTC1-dependent gene transcription by beta-amyloid (Abeta) in response to cAMP and Ca(2+) signals is mediated by reduced calcium influx and disruption of PP2B/calcineurin-dependent CRTC1 dephosphorylation at Ser151. Consistently, expression of CRTC1 or active CRTC1 S151A and calcineurin mutants reverse the deficits on CRTC1 transcriptional activity in APP(Sw,Ind) neurons. Inhibition of calcium influx by pharmacological blockade of L-type voltage-gated calcium channels (VGCCs), but not by blocking NMDA or AMPA receptors, mimics the decrease on CRTC1 transcriptional activity observed in APP(Sw,Ind) neurons, whereas agonists of L-type VGCCs reverse efficiently these deficits. Consistent with a role of C...Continue Reading

Citations

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