Missense mutations in the PRESENILIN1 (PSEN1) gene frequently underlie familial 
Alzheimer's disease (FAD). Nonsense and most splicing mutations result in the 
synthesis of truncated peptides, and it has been assumed that truncated PSEN1 
protein is functionless so that heterozygotes for these mutations are 
unaffected. Some FAD mutations affecting PSEN1 mRNA splicing cause loss of exon 
8 or 9 sequences while maintaining the reading frame. We attempted to model 
these exon-loss mutations in zebrafish embryos by injecting morpholino antisense 
oligonucleotides (morpholinos) directed against splice acceptor sites in 
zebrafish psen1 transcripts. However, this produced cryptic changes in splicing 
potentially forming mRNAs encoding truncated presenilin proteins. Aberrant 
splicing in the region between exons 6 and 8 produces potent dominant negative 
effects on Psen1 protein activity, including Notch signalling, and causes a 
hydrocephalus phenotype. Reductions in Psen1 activity feedback positively to 
increase psen1 transcription through a mechanism apparently independent of 
gamma-secretase. We present evidence that the dominant negative effects are 
mediated through production of truncated Psen1 peptides that interfere with the 
normal activity of both Psen1 and Psen2. Mutations causing such truncations 
would be dominant lethal in embryo development. Somatic cellular changes in 
ageing cells that interfere with PSEN1 splicing, or otherwise cause protein 
truncation, might contribute to sporadic Alzheimer's disease, cancer and other 
diseases.