Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function

We compare here the neurodegenerative processes observed in the hippocampus of bitransgenic mice with chronically altered levels of cAMP-response element-binding protein (CREB) function. The combination of genome-wide transcriptional profiling of degenerating hippocampal tissue with microscopy analyses reveals that the sustained inhibition of CREB function in A-CREB mice is associated with dark neuron degeneration, whereas its strong chronic activation in VP16-CREB mice primarily causes excitotoxic cell death and inflammation. Furthermore, the meta-analysis with gene expression profiles available in public databases identifies relevant common markers to other neurodegenerative processes and highlights the importance of the immune response in neurodegeneration. Overall, these analyses define the ultrastructural and transcriptional signatures associated with these two forms of hippocampal neurodegeneration, confirm the importance of fine-tuned regulation of CREB-dependent gene expression for CA1 neuron survival and function, and provide novel insight into the function of CREB in the etiology of neurodegenerative processes. © 2010 Macmillan Publishers Limited All rights reserved.The work at AB and LMV laboratory was supported by the European Commission Coordination Action ENINET (contract number LSHM-CT-2005-19063), the Spanish Ministry of Science and Innovation grants BFU2005-00286, CSD2007-00023, and SAF2008-00611, the Generalitat Valenciana grant GVPRE/2008/365, and the Fundació La Marató de TV3 grant 063510. The work at RL laboratory was supported by the Spanish Ministry of Science and Innovation grant BFU2006-01896 and the Junta de Comunidades de Castilla-La Mancha grant PAI08-0174-6967.Peer Reviewe