Alteration of caspases and other apoptosis regulatory proteins in Down syndrome

Apoptosis has been implicated in the selective neuronal loss of Down syndro me (DS). Apoptosis activates a family of cysteine proteases with specificit y for aspartic acid residues referred to as caspases that play a key role i n dismantling a cell committed to die. Caspase activity is regulated by a v ariety of proteins that possess a domain resembling the prodomains of caspa ses. Little is known, however, about the changes of caspases and their regu latory proteins in DS. Here, we investigated levels of nine such different proteins by western blot technique in frontal cortex and cerebellum of cont rol and DS subjects. The protein levels of DFF45 (DNA fragmentation factor 45), and FLIP (FADD like interleukin-1 beta -converting enzyme inhibitory p roteins) were significantly decreased whereas that of RICK (RIP-like intera cting CLARP kinase) increased in both regions of DS. In contrast, cytochrom e c, Apaf-1 (apoptosis protease activating factor-1), procaspase-9 and ARC (apoptosis repressor with caspase recruitment domain) were unchanged. Proca spase-3 and -8 were significantly decreased in frontal cortex but no signif icant change was observed in cerebellum. Regression analysis revealed no co rrelation between postmortem interval and levels of the investigated protei ns. However, inconsistent correlation was found between age and levels of p roteins as well as amongst the density of individual proteins. These findin gs demonstrate that dysregulation of apoptotic proteins does exist in DS br ain and may underlie the neuropathology of DS. The study further suggests t hat apoptosis in DS may occur via the death receptor pathway independent of cytochrome, c. Hence, therapeutic strategies that target caspase activatio n may prove useful in combating neuronal loss in this disorder.