TY - JOUR
T1 - The aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-catenin-independent mechanisms
AU - Xia, Xuefeng
AU - Wang, Pei
AU - Sun, Xiaoyan
AU - Soriano, Salvador
AU - Shum, Wan Kyng
AU - Yamaguchi, Haruyasu
AU - Trumbauer, Myrna E.
AU - Takashima, Akihiko
AU - Koo, Edward H.
AU - Zheng, Hui
PY - 2002/6/25
Y1 - 2002/6/25
N2 - 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 AβX-40 and AβX-42 in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Aβ.
AB - 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 AβX-40 and AβX-42 in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Aβ.
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U2 - 10.1073/pnas.132045399
DO - 10.1073/pnas.132045399
M3 - Article
C2 - 12070348
AN - SCOPUS:0037173071
VL - 99
SP - 8760
EP - 8765
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 13
ER -