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 (hPS1Deltacat) essential for beta-catenin interaction. We show here that although hPS1Deltacat 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 (Abeta). Further, by measuring the levels of endogenous Abeta(X-40) and Abeta(X-42) in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Abeta.
Xia
Xuefeng
X
Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
Wang
Pei
P
Sun
Xiaoyan
X
Soriano
Salvador
S
Shum
Wan-Kyng
WK
Yamaguchi
Haruyasu
H
Trumbauer
Myrna E
ME
Takashima
Akihiko
A
Koo
Edward H
EH
Zheng
Hui
H
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006868:Hydrolysis; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1; D051880:Receptors, Notch; D015534:Trans-Activators; D051176:beta Catenin
D016229:Amyloid beta-Peptides; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051880:Receptors, Notch; D015534:Trans-Activators; D051176:beta Catenin; D001224:Aspartic Acid