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

doi:10.1073/pnas.132045399

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

^*Huffington Center on Aging, ^†Department of Molecular and Cellular Biology, and ^**Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; ^‡Laboratory for Alzheimer's Disease, The Brain Science Institute of The Institute of Physical and Chemical Research, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan; ^§Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093; ^¶Gunma University School of Health Sciences, Showa-machi, Maebashi, Gunma 371, Japan; and ^‖Merck Research Laboratories, Rahway, NJ 07065

Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved May 7, 2002 (received for review January 25, 2002)

Abstract

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.

Footnotes

↵ ‡‡ To whom reprint requests should be addressed at: Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, M320, Houston, TX 77030. E-mail: huiz{at}bcm.tmc.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

PS1,

presenilin 1;

APP,

β-amyloid precursor protein;

TM,

transmembrane;

Aβ,

β-amyloid peptides;

NTF,

N-terminal fragment;

CTF,

C-terminal fragment;

CNS,

central nervous system;

NICD,

Notch intracellular domain;

En,

embryonic day n