The aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-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 (hPS1Δcat) essential for β-catenin interaction. We show here that although hPS1Δcat 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 β-amyloid precursor protein (APP) and the generation of β-amyloid peptides (Aβ). Further, by measuring the levels of endogenous Aβ(X-40) and Aβ(X-42) in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Aβ.