-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.

Download full-text


Available from: Alfredo J Miñano-Molina, Oct 09, 2015
43 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Neurobiology of Disease 05/2014; 72. DOI:10.1016/j.nbd.2014.05.019 · 5.08 Impact Factor
    • "CRTCs (CREB-regulated transcription coactivators, also known as TORCs) may also regulate CREB-dependent gene expression (Conkright et al., 2003). CRTC1, a brain-enriched isoform of CRTC, regulates dendritic morphology in developing cortical neurons (Li et al., 2009) and IEG expression in mature hippocampal neurons (Espana et al., 2010; Nonaka et al., personal communication). Two different families of coactivators, TCF (ternary complex factor) (Treisman, 1994) and MKL (megakaryoblastic leukemia or megakaryocytic acute leukemia, MAL) (Miralles et al., 2003; Selvaraj and Prywes, 2003), are known as SRF cofactors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Neurons make contact with each other and form neuronal networks. The synapse, the site of contact between 2 neurons, has the ability to dynamically modify functional efficiency and connectivity in response to spatially and temporally specific patterns of neuronal activity. Such plastic ability of the synapse is believed to be indispensable for our cognitive functions, including learning and memory. In this review, I summarize our current understanding of the molecular and cellular mechanisms underlying synaptic plasticity. Lines of evidence have indicated that postsynaptic regulations of AMPA-type glutamate receptors (AMPA-Rs) are crucial for synaptic plasticity. Synaptic plasticity can be long-lasting if the local synaptic modifications interact with activity-dependent, newly synthesized plasticity-related molecules in the neuronal cell body. Recently, we found that the activity-regulated memory-related protein Arc is involved in synapse-specific regulation of AMPA-Rs. This Arc-dependent mechanism, together with other molecular mechanisms, possibly helps maintain the contrast of synaptic strength between strong and weak synapses, thus, promoting the formation of long-term memory.
    Brain and nerve = Shinkei kenkyū no shinpo 10/2013; 65(10):1171-1178.
  • Source
    • "However, papaverine treatment did not change pCRTC1 (Ser151) levels in either genotype. As BDNF transcription is CRTC1-dependent (Espana et al., 2010), this result is consistent with the finding that BDNF levels were not altered by papaverine treatment. Even though CRTC1 levels are reduced in R6/1 mice hippocampus, and papaverine treatment did not affect its phosphorylation levels, it was able to improve recognition and spatial memories in R6/1 mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Huntington's disease (HD) causes motor disturbances, preceded by cognitive impairment, in patients and mouse models. We showed that increased hippocampal cAMP-dependent protein kinase (PKA) signaling disrupts recognition and spatial memories in R6 HD mouse models. However, unchanged levels of hippocampal phosphorylated (p) cAMP-responsive element binding protein (CREB) suggested unaltered nuclear PKA activity in R6 mice. Here, we extend this finding by showing that nuclear pPKA catalytic subunit (Thr197) and pPKA substrates levels were unaltered in the hippocampus of R6/1 mice. Phosphodiesterases (PDEs) play an important role in the regulation of PKA activity. PDE10A, a cAMP/cGMP dual-substrate PDE, was reported to be restricted to the nuclear region in non-striatal neurons. Using cell fractionation we confirmed that PDE10A was enriched in nuclear fractions, both in wild-type and R6/1 mice hippocampus, without differences in its levels or intracellular distribution between genotypes. We next investigated whether inhibition of PDE10 with papaverine could improve cognitive function in HD mice. Papaverine treatment improved spatial and object recognition memories in R6/1 mice, and significantly increased pGluA1 and pCREB levels in R6/1 mice hippocampus. Papaverine likely acted through the activation of the PKA pathway since the phosphorylation level of distinct cGMP-dependent kinase (cGK) substrates was not modified in either genotype. Moreover, hippocampal cAMP, but not cGMP, levels were increased after acute papaverine injection. Our results show that inhibition of PDE10 improves cognition in R6 mice, at least in part through increased GluA1 and CREB phosphorylation. Thus, PDE10 might be a good therapeutic target to improve cognitive impairment in HD. © 2013 Wiley Periodicals, Inc.
    Hippocampus 08/2013; 23(8). DOI:10.1002/hipo.22128 · 4.16 Impact Factor
Show more