CREB-regulated transcription coactivator 1-dependent transcription in Alzheimer's disease mice

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Abstract

Background/Aims: Long-term memory requires fine-tuning regulation of gene expression in specific neural circuits of the brain. Transcriptional regulation of gene programs is a key mechanism for memory storage and its deregulation may contribute to synaptic and cognitive dysfunction in memory disorders. The molecular mechanisms underlying changes on activity-dependent gene expression in Alzheimer's disease (AD) are largely unknown. Methods: We analyzed the expression of activity-dependent genes regulated by the cAMP response element binding protein (CREB) and activation of CREB and its coactivator CREB-regulated transcription coactivator 1 (CRTC1) in control and mutant β-amyloid precursor protein (APP Sw,Ind; Swedish and Indiana mutations) transgenic mice. Results: Gene expression analyses revealed specific downregulation of a subset of well-known activity-induced CREB-dependent genes, including c-fos, Bdnf and Nr4a2, in the hippocampus of memory-impaired APP Sw,Ind transgenic mice. Activity-dependent CREB transcription induced by calcium/cAMP signals is disrupted through a mechanism involving deregulation of calcium/calcineurin-mediated dephosphorylation and activation of CRTC1. Expression of CRTC1 and pharmacological activation of L-type voltage-gated calcium channels reverse the deficits in CRTC1-mediated transcription in APP Sw,Ind neurons. Conclusion: Our results suggest that CRTC1 dysfunction caused by Aβ accumulation underlies changes in gene expression required for hippocampal-dependent memory in AD transgenic mice. Copyright © 2012 S. Karger AG, Basel.
Original languageEnglish
Pages (from-to)250-252
JournalNeurodegenerative Diseases
Volume10
DOIs
Publication statusPublished - 1 Apr 2012

Keywords

  • Alzheimer's disease
  • Amyloid
  • Gene expression
  • Memory
  • Signaling
  • cAMP response element binding protein

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