Journal
NEURODEGENERATIVE DISEASES
Volume 10, Issue 1-4, Pages 250-252Publisher
KARGER
DOI: 10.1159/000333341
Keywords
Alzheimer's disease; Memory; Amyloid; cAMP response element binding protein; Gene expression; Signaling
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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 beta-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 A beta accumulation underlies changes in gene expression required for hippocampal-dependent memory in AD transgenic mice. Copyright (C) 2012 S. Karger AG, Basel
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