The majority of early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genes, PS1 and PS2, located on chromosome 14 and 1, respectively. Using two highly specific antibodies against nonoverlapping epitopes of the PS1-encoded polypeptide, termed presenilin 1 (PS1), we document that the preponderant PS1-related species that accumulate in cultured mammalian cells, and in the brains of rodents, primates, and humans are ~27-28 kDa N-terminal and ~16-17 kDa C-terminal derivatives. Notably, a FAD-linked PS1 variant that lacks exon 9 is not subject to endoproteolytic cleavage. In brains of transgenic mice expressing human PS1, ~17 kDa and ~27 kDa PS1 derivatives accumulate to saturable levels, and at ~1:1 stoichiometry, independent of transgene-derived mRNA. We conclude that PS1 is subject to endoproteolytic processing in vivo.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health grants AG0514, NS20471, and AG05689 to M. S. S., United States Public Health Service grants AG11508 and AG09464 to S. E. G., the National Cancer Institute, Department of Health and Human Services, under contract with Advanced BioScience Laboratories, and by grants from the Adler Foundation and Develbiss Fund. S. S. S. is the recipient of an Alzheimer's Association Zenith Award.