Presenilin–1 is Processed into Two Major Cleavage Products in Neuronal Cell Lines

Presenilin 1 (PS–1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). Using PS–1 transfected SHSY5Y neuroblastoma cells, we have demonstrated by immunodetection, using polyclonal antibodies, that PS–1 is processed to give two fragments: an N–terminal 28 kDa fragment, and a C–terminal 18 kDa fragment. In a number of non-transfected cell types, most PS–1 is detected as the cleaved products. The molecular weights of the PS–1 cleavage products suggest that the cleavage point will most probably be within a region of the hydrophilic loop domain coded for by either exon 8 or 9 of the PS–1 gene. The clustering of FAD mutations within exon 8 strongly suggests that it encodes a key functional domain. It seems likely that the cleavage of PS–1 is crucial to some aspect of its functionality. An understanding of this process will give insights into the pathology of AD, and may offer new opportunities for therapeutic intervention.