Expression of transcription factors c-Fos, c-Jun, CREB-1 and ATF-2, and caspase-3 in relation with abnormal tau deposits in Pick's disease.
Hyper-phosphorylated tau deposition in Pick bodies and neuron loss are major hallmarks of Pick's disease (PiD). However, there is no regional correlation between neuron loss and Pick bodies, as illustrated in dentate gyrus, where Pick bodies are present in almost every neuron, whereas cell death, if present, is not a major event. In order to better understand the possible role of selected transcription factors and members of the caspase family in cell death and cell survival, immunohistochemistry to c-Fos, c-Jun, CREB-1, ATF-2; c-Fos(P), c-Jun(P) and CREB-1(P); and procaspase-8, procaspase-3 and active (cleaved) caspase-3 immunohistochemistry was carried out in the frontal cortex and hippocampus. Increased expression of c-Fos, c-Jun, CREB-1 and ATF-2 was observed in PiD cases. Increased c-Fos(P), c-Jun(P) and CREB-1(P) was also found in the nuclei of neurons in diseased brains. Interestingly, c-Fos but not c-Fos(P) co-localized in many Pick bodies, as observed by double labelling-immunofluorescence and confocal microscopy. Pro-caspase-8 and pro-caspase-3 were increased in PiD. Moreover, granular active caspase-3 was observed in the nuclei as was aggregated active caspase-3 in the cytoplasm of neurons in PiD. Finally, double-labelling immunofluorescence and confocal microscopy disclosed co-localization of cytoplasmic active caspase-3 only in neurons with Pick bodies. Together, these findings show an increased expression of selected transcription factors and active (phosphorylated) forms in PiD, c-Fos sequestration in Pick bodies, and increased active caspase-3 expression in relation with Pick bodies. Since all these findings were observed equally in neurons of both vulnerable regions (frontal cortex) and resistant regions (dentate gyrus), it may be suggested that transcription factors are only barely related with cell death. Active caspase-3 is associated with tau deposition in Pick bodies, but it is not a marker of cell death in the dentate gyrus in PiD. The present findings are in line with the previous studies showing tau products cleaved by caspase-3, as recognized by specific tau-cleaved antibodies, in Alzheimer's disease and other tauopathies.
Nieto-Bodelón
María
M
Unitat de Neuropatologia Experimental, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain.
Santpere
Gabriel
G
Torrejón-Escribano
Benjamín
B
Puig
Berta
B
Ferrer
Isidre
I
D051696:Activating Transcription Factors / Q000096:biosynthesis; D000368:Aged; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D020774:Pick Disease of the Brain / Q000378:metabolism* / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis*; D016875:tau Proteins / Q000378:metabolism*
D051696:Activating Transcription Factors; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D016875:tau Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases