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The presenilin 1 ( PSEN1)  L271V mutation causes early-onset familial Alzheimer’s disease by disrupting the alternative splicing of the  PSEN1  gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1 ∆exon8 ). We previously reported that PS1 L271V increased amyloid beta (Aβ) 42/40 ratios, while PS1 ∆exon8  reduced Aβ42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1 ∆exon8  did not rescue Aβ generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1 ∆exon8  is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1 ∆exon8   in vivo  by crossing PS1 ∆exon8  transgenics with either PS1-null or Dutch APP E693Q  mice. As a control, we crossed APP E693Q  with mice expressing a deletion in an adjacent exon (PS1 ∆exon9 ). PS1 ∆exon8  did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function  in vivo . We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1 ∆exon8  interacts with nicastrin, participating in the γ–secretase complex formation. These data support that catalytically inactive PS1 ∆exon8  is generated physiologically and participates in protein-protein interactions.

Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1−/− phenotype and forms complexes with wildtype PS1 and nicastrin