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

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 ␤-amyloid precursor protein (APP Sw,Ind ). Suppression of CRTC1-dependent gene transcription by ␤-amyloid (A␤) in response to cAMP and Ca2ϩ 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 A␤-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 A␤ could disrupt cognition by affecting CRTC1 function.

[P3–175]: Crtc1 Function During Memory Encoding Is Disrupted in Neurodegeneration

“…We found a time-dependent differential induction of CREB target Nr4a family genes Nr4a1-3 in the hippocampus, a result that agrees with the requirement of Nr4a genes for contextual memory (44,55). CRTC1-mediated transcription may involve CRTC1 dephosphorylation at Ser151, a critical event for activityinduced CREB-mediated transcription (33,36). Since the histone deacetylase CBP mediates CREBdependent transcription through cooperative interactions with CRTC2 and CREB (26), it is possible that CRTC1 dephosphorylation and nuclear translocation could mediate its recruitment to CREB target promoters through cooperative interactions with CBP and CREB.…”

P1–100: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

“…The expression of some of these IEGs is reduced in AD, as has been shown by in vitro and in vivo experiments (5, 7-9, 11, 12). Most recently, it was reported that gene transcription, mediated by the cAMP-response element binding protein (CREB)-regulated transcription coactivator CRTC1, is impaired in a mouse model of AD (13), further suggesting that Aβ-induced memory deficits may be due to alterations in signaling transduction pathways. CREB is a key immediate early gene involved in learning and memory.…”

Rapid Identification of Bioactive Compounds Reducing the Production of Amyloid β-Peptide (Aβ) from South African Plants Using an Automated HPLC/SPE/HPLC Coupling System

“…While Aβ40 is the predominant cleavage product, the less abundant Aβ42 represents a longer and more amyloidogenic form of Aβ. Moreover, increased cerebrocortical Aβ42 appears to closely correlate with synaptic dysfunction associated with AD (España et al, 2010). The biological study on the action mechanism of compounds 1-4 DOI: 10.4062/biomolther.2011.19.1.090 is in progress.…”