Open AccessThe aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-catenin-independent mechanisms
Author(s) -
Xuefeng Xia,
Pei Wang,
Xiaoyan Sun,
Salvador Soriano,
Wan Kyng Shum,
Hideyo Yamaguchi,
Myrna E. Trumbauer,
Akihiko Takashima,
Edward H. Koo,
Hui Zheng
Publication year - 2002
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.132045399
Subject(s) - presenilin , biology , genetically modified mouse , amyloid (mycology) , transgene , biochemistry , catenin , amyloid precursor protein , mutation , microbiology and biotechnology , alzheimer's disease , gene , medicine , wnt signaling pathway , botany , disease
To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two humanPS1 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 thePS1 -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 AβX-40 and AβX-42 in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Aβ.