-Amyloid Disrupts Activity-Dependent Gene Transcription Required for Memory through the CREB Coactivator CRTC1

Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2010; 30(28):9402-10. DOI: 10.1523/JNEUROSCI.2154-10.2010
Source: PubMed


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 CRTC1 on Abeta-induced synaptic and memory dysfunction, we demonstrate a selective reduction of CRTC1-dependent genes related to memory (Bdnf, c-fos, and Nr4a2) coinciding with hippocampal-dependent spatial memory deficits in APP(Sw,Ind) mice. These findings suggest that CRTC1 plays a key role in coupling synaptic activity to gene transcription required for hippocampal-dependent memory, and that Abeta could disrupt cognition by affecting CRTC1 function.

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Available from: Alfredo J Miñano-Molina,
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    • "Accordingly, dysregulation of CREB activity has been implicated in various CNS disorders, including AD, Huntington's disease, Parkinson's disease, ischaemia and addiction (Walton & Dragunow , 2000; Nucifora et al., 2001; Ma et al., 2007; Sawamura et al., 2008). Ab-mediated CREB dysfunction leads to reductions in the levels of synaptic plasticity-related genes, such as Bdnf, Nr4a2 and c-fos (Espana et al., 2010). Notably, the expression of the DARPP-32 T153A mutant blocked the decrease in c-fos expression by restoring CREB phosphorylation (Fig. 5A "
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    • "Recent evidence from the Saura group indicates that Nurr1 levels are decreased in an AD mouse model as well as in late-stage AD patients (España et al., 2010; Parra-Damas et al., 2014), and it has been reported that Nur77 levels decrease with age in an APP/PS1 mouse model of AD (Dickey et al., 2003). However, a direct role of Nurr1 in AD pathogenesis has yet to be studied. "
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