Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stages.
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.
Institut de Neurociències, Department de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona 08193, Spain, and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) and Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Barcelona 08907, Spain.
Arnaldo
A
Parra-Damas
Jorge
J
Valero
Meng
M
Chen
Judit
J
España
Elsa
E
Martín
Isidro
I
Ferrer
José
J
Rodríguez-Alvarez
Carlos A
CA
Saura
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; C519509:Crtc1 protein, mouse; D014157:Transcription Factors
CREB; TORC; gene expression; memory; neurodegeneration; β-amyloid