Zebrafish (Danio rerio) Presenilin Promotes Aberrant Amyloid β-Peptide Production and Requires a Critical Aspartate Residue for Its Function in Amyloidogenesis

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Abstract
Alzheimer's disease (AD) is characterized by the invariable accumulation of senile plaques composed of amyloid β-peptide (Aβ). Mutations in three genes are known to cause familial Alzheimer's disease (FAD). The mutations occur in the genes encoding the β-amyloid precursor protein (βAPP) and presenilin (PS1) and PS2 and cause the increased secretion of the pathologically relevant 42 amino acid Aβ42. We have now cloned the zebrafish (Danio rerio) PS1 homologue (zf-PS1) to study its function in amyloidogenesis and to prove the critical requirement of an unusual aspartate residue within the seventh putative transmembrane domain. In situ hybridization and reverse PCR reveal that zf-PS1 is maternally inherited and ubiquitously expressed during embryogenesis, suggesting an essential housekeeping function. zf-PS1 is proteolytically processed to produce a C-terminal fragment (CTF) of approximately 24 kDa similar to human PS proteins. Surprisingly, wt zf-PS1 promotes aberrant Aβ42 secretion like FAD associated human PS1 mutations. The unexpected pathologic activity of wt zf-PS1 may be due to several amino acid exchanges at positions where FAD-associated mutations have been observed. The amyloidogenic function of zf-PS1 depends on the conserved aspartate residue 374 within the seventh putative transmembrane domain. Mutagenizing this critical aspartate residue abolishes endoproteolysis of zf-PS1 and inhibits Aβ secretion in human cells. Inhibition of Aβ secretion is accompanied by the accumulation of C-terminal fragments of βAPP, suggesting a defect in γ-secretase activity. These data provide further evidence that PS proteins are directly involved in the proteolytic cleavage of βAPP and demonstrate that this function is evolutionarily conserved.