-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
    • "Upon phosphorylation by salt-inducible kinase, CRTC1 is shuttled back to the cytoplasm (Takemori and Okamoto 2008). Therefore, CRTC1-dependent gene expression is tightly regulated by its subcellular localization and Aβ has been shown to negatively affect CRTC1-dependent gene transcription (Espana et al. 2010). This led us to investigate whether the accumulation of intraneuronal Aβ is sufficient to impede CRTC1 nuclear translocation in this rat model. "
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    ABSTRACT: In Alzheimer disease (AD), the accumulation of amyloid beta (Aβ) begins decades before cognitive symptoms and progresses from intraneuronal material to extracellular plaques. To date, however, the precise mechanism by which the early buildup of Aβ peptides leads to cognitive dysfunction remains unknown. Here, we investigate the impact of the early Aβ accumulation on temporal and frontal lobe dysfunction. We compared the performance of McGill-R-Thy1-APP transgenic AD rats with wild-type littermate controls on a visual discrimination task using a touchscreen operant platform. Subsequently, we conducted studies to establish the biochemical and molecular basis for the behavioral alterations. It was found that the presence of intraneuronal Aβ caused a severe associative learning deficit in the AD rats. This coincided with reduced nuclear translocation and genomic occupancy of the CREB co-activator, CRTC1, and decreased production of synaptic plasticity-associated transcripts Arc, c-fos, Egr1, and Bdnf. Thus, blockade of CRTC1-dependent gene expression in the early, preplaque phase of AD-like pathology provides a molecular basis for the cognitive deficits that figure so prominently in early AD.
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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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    ABSTRACT: Toxicity induced by aberrant protein aggregates in Alzheimer's disease (AD) causes synaptic disconnection and concomitant progressive neurodegeneration that eventually impair cognitive function. cAMP-response element-binding protein (CREB) is a transcription factor involved in the molecular switch that converts short-term to long-term memory. Although disturbances in CREB function have been suggested to cause memory deficits in both AD and AD animal models, the mechanism of CREB dysfunction is still unclear. Here, we show that the dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32), a key inhibitor of protein phosphate-1 (PP-1) that regulates CREB phosphorylation, is cleaved by activated calpain in both AD brains and neuronal cells treated with amyloid-β or okadaic acid, a protein phosphatase-2A inhibitor that induces tau hyperphosphorylation and neuronal death. We found that DARPP-32 is mainly cleaved at Thr(153) by calpain and that this cleavage of DARPP-32 reduces CREB phosphorylation via loss of its inhibitory function on PP1. Our results suggest a novel mechanism of DARPP-32-CREB signalling dysregulation in AD. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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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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    ABSTRACT: Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.
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