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.
Valor
L M
LM
Instituto de Neurociencias de Alicante (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, Apt. 18, Sant Joan d'Alacant, Alicante 03550, Spain.
Jancic
D
D
Lujan
R
R
Barco
A
A
D000818:Animals; D017209:Apoptosis; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure*; D007249:Inflammation / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
C508138:A-CREB protein; D017362:Cyclic AMP Response Element-Binding Protein; D017405:Herpes Simplex Virus Protein Vmw65; D011993:Recombinant Fusion Proteins