The aspartate-257 of presenilin 1 is indispensable for mouse development and production of [beta]-amyloid peptides through [beta]-catenin-independent mechanisms

To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two human PS1 alleles: one with the aspartate to alanine mutation at residue 257 (hPS1D257A) that impairs the proteolytic activity of PS1, and the other deleting amino acids 340-371 of the hydrophilic loop sequence (hPS1[DELTA]cat) essential for [beta]-catenin interaction. We show here that although hPS1[DELTA]cat is fully competent in rescuing the PS1-null lethal phenotype, hPS1D257A does not exhibit developmental activity. hPS1D257A also leads to the concurrent loss of the proteolytic processing of Notch and [beta]-amyloid precursor protein (APP) and the generation of [beta]-amyloid peptides (A[beta]). Further, by measuring the levels of endogenous A[[beta].sub.x-40] and A[[beta].sub.x-42] in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted A[beta].