title: CREB-regulated transcription coactivator 1-dependent transcription in Alzheimer's disease mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Our results suggest that CRTC1 dysfunction caused by Aβ accumulation underlies changes in gene expression required for hippocampal-dependent memory in AD transgenic mice.
authors.affiliation: Institut de Neurociències, Departament Bioquímica i Biologia Molecular, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Bellaterra, Spain. carlos.saura@uab.es
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Saura
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D000242:Cyclic AMP / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C500984:CRTC1 protein, human; D010446:Peptide Fragments; D014157:Transcription Factors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013779:Tetrodotoxin; D000242:Cyclic AMP; D019703:Calcineurin; D002118:Calcium