Mutations on presenilins are responsible for most of familial forms of Alzheimer's disease. These holoproteins undergo rapid maturation by presenilinase mainly in the endoplasmic reticulum, leading to the production of N- and C-terminal fragments. We show first that overexpression of the presenilinase-derived maturation product of presenilin 2 (CTF-PS2) increases Aβ recovery, the production of which is almost abolished by a caspase 3 inhibitor and increased by staurosporine. This and the observation that the apoptotic inducer staurosporine enhances CTF-PS2 degradation clearly link CTF-PS2 to apoptotic cascade effectors. This prompted us to analyze the putative ability of CTF-PS2 to modulate cell death. CTF-PS2 overexpression decreases cell viability and augments both caspase 3 activity and immunoreactivity. This is accompanied by lowered bcl2-like immunoreactivity and increased poly(ADP-ribose) polymerase cleavage and cytochrome c translocation into the cytosol. Interestingly, CTF-PS2-induced caspase 3 activation is prevented by pifithrin-α, a selective blocker of p53 transcriptional activity. On line with the latter data, CTF-PS2 drastically increases p53 immunoreactivity and transcriptional activity. Of most interest is our observation that CTF-PS2 expression also triggers increased caspase 3 activity and immunoreactivity in fibroblasts in which presenilins had been deleted. Therefore, CTF-PS2 could modulate cell death out of the NTF/CTF heterodimeric complex thought to correspond to the biologically functional entity. This is the first direct demonstration that CTF-PS2 could exhibit some of its functions in the absence of the presenilin 2 N-terminal fragment (NTF-PS2) counterpart derived from the presenilinase cleavage.
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