Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stages
Parra-Damas, Arnaldo (Universitat Autònoma de Barcelona. Institut de Neurociències)
Valero, Jorge (Universitat Autònoma de Barcelona. Institut de Neurociències)
Chen, Meng (Universitat Autònoma de Barcelona. Institut de Neurociències)
España Agustí, Judit (Universitat Autònoma de Barcelona. Institut de Neurociències)
Martín, Elsa (Universitat Autònoma de Barcelona. Institut de Neurociències)
Ferrer, Isidro (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Rodríguez Álvarez, José (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Saura Antolín, Carlos (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2014
Abstract:	Cognitive decline is associated with gene expression changes in the brain, but the transcriptional mechanisms underlying memory impairments in cognitive disorders, such as Alzheimer's disease (AD), are largely unknown. Here, we aimed to elucidate relevant mechanisms responsible for transcriptional changes underlying early memory loss in AD by examining pathological, behavioral, and transcriptomic changes in control and mutant β-amyloid precursor protein(APPSw,Ind) transgenic mice during aging. Genome-wide transcriptome analysis using mouse microarrays revealed deregulation of a gene network related with neurotransmission, synaptic plasticity, and learning/memory in the hippocampus of APPSw,Ind mice after spatial memory training. Specifically, APPSw,Ind mice show changes on a cAMP-responsive element binding protein(CREB)- regulated transcriptional program dependent on the CREB-regulated transcription coactivator-1 (Crtc1). Interestingly, synaptic activity and spatial memory induces Crtc1 dephosphorylation (Ser151), nuclear translocation, and Crtc1-dependent transcription in the hippocampus, and these events are impaired in APPSw,Ind mice at early pathological and cognitive decline stages. CRTC1-dependent genes and CRTC1 levels are reduced in human hippocampus at intermediate Braak III/IV pathological stages. Importantly, adeno-associated viral-mediated Crtc1 overexpression in the hippocampus efficiently reverses Aβ-induced spatial learning and memory deficits by restoring a specific subset of Crtc1 target genes. Our results reveal a critical role of Crtc1-dependent transcription on spatial memory formation and provide the first evidence that targeting brain transcriptome reverses memory loss in AD.
Grants:	European Commission 200611
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	β-amyloid ; CREB ; Gene expression ; Memory ; Neurodegeneration ; TORC ; β-amiloide ; Expressió gènica ; Memòria ; Neurodegeneració
Published in:	The Journal of neuroscience, Vol. 34 No. 17 (April 2014) , p. 5776-5787, ISSN 1529-2401

DOI: 10.1523/JNEUROSCI.5288-13.2014
PMID: 24760838

12 p, 2.7 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles