Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta-peptide production and requires a critical aspartate residue for its function in amyloidogenesis

Alzheimer's disease (AD) is characterized by the invariable accumulation of senile plaques composed of amyloid beta-peptide (A beta). Mutations in thr ee genes are known to cause familiar Alzheimer's disease (FAD). The mutatio ns occur in the genes encoding the beta-amyloid precursor protein (beta APP ) and presenilin (PSI) and PS2 and cause the increased secretion of the pat hologically relevant 42 amino acid A beta 42. We have now cloned the zebraf ish (Danio rerio) PSI homologue (zf-PS1) to study its function in amyloidog enesis and to prove the critical requirement of an unusual aspartate residu e within the seventh putative transmembrane domain. In situ hybridization a nd reverse PCR reveal that zf-PS1 is maternally inherited and ubiquitously expressed during embryogenesis, suggesting an essential housekeeping functi on. zf-PS1 is proteolytically processed to produce a C-terminal fragment (C TF) of approximately 24 kDa similar to human PS proteins. Surprisingly, wt zf-PS1 promotes aberrant A beta 42 secretion like FAD associated human PS1 mutations. The unexpected pathologic activity of wt zf-PS1 may be due to se veral amino acid exchanges at positions where FAD-associated mutations have been observed. The amyloidogenic function of zf-PS1 depends on the conserv ed aspartate residue 374 within the seventh putative transmembrane domain. Mutagenizing this critical aspartate residue abolishes endoproteolysis of z f-PS1 and inhibits A beta secretion in human cells. Inhibition of A beta se cretion is accompanied by the accumulation of C-terminaI fragments of beta APP, suggesting a defect in gamma-secretase activity. These data provide fu rther evidence that PS proteins are directly involved in the proteolytic cl eavage of beta APP and demonstrate that this function is evolutionarily con served.