Caspase cleavage of exon 9 deleted presenilin‐1 is an early event in apoptosis induced by calcium ionophore A 23187 in SH‐SY5Y neuroblastoma cells

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Abstract
Presenilins (PSs) are mutated in a majority of familial Alzheimer disease (FAD) cases. Mutated PSs may cause FAD by a number of pro‐apoptotic mechanisms, or by regulating γ‐secretase activity, a protease involved in β‐amyloid precursor protein processing to the neurotoxic β‐amyloid peptide. Besides their normal endoproteolytic processing, PSs are substrates for caspases, being cleaved to alternative N‐terminal and C‐terminal fragments. So far little is known about the role of PSs cleavage in the apoptotic machinery. Here, we used SH‐SY5Y neuroblastoma cells stably transfected with wild‐type or exon 9 deleted presenilin 1 (PS1) in a time‐course study after the exposure to the calcium ionophore A23187. During and after exposure to A 23187, intracellular calcium levels were higher in exon 9 deleted PS1 cells as compared with non‐transfected and wild‐type PS1 transfected cells. Cell death and the enrichment of apoptotic cells after A23187 exposure were increased by overexpression of exon 9 deleted PS1 as compared with the control cell lines. Wild‐type PS1 cells were compared with exon 9 deleted PS1 cells and the temporal relationship between PS1 and other caspase substrates cleavages was analyzed. Exon 9 deleted PS1 cells exhibited a higher caspase‐3 activation and a greater cleavage of PS1 and poly(ADP‐ribose) polymerase (PARP) compared with wild‐type PS1 cells. Exon 9 deleted PS1 cleavage occurred earlier than other caspase substrate cleavages (i.e., PARP and gelsolin), simultaneous with minimum detectable caspase‐3 activation. Therefore, alternative cleavage of PS1 may play an important role for the regulation of the proteolytic cascade activated during apoptosis. J. Neurosci. Res. 66:122–134, 2001.