TY - JOUR
T1 - The role of β-catenin stability in mutant PS1-associated apoptosis
AU - Weihl, Conrad C.
AU - Miller, Richard J.
AU - Roos, Raymond P.
PY - 1999/8/20
Y1 - 1999/8/20
N2 - Most early onset cases of familial Alzheimer's disease (FAD) are caused by mutations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to increased β-amyloid formation and induce apoptosis when expressed in vitro. Recently, PS1 has been reported to associate with β-catenin, an armadillo repeat protein. PS1 may regulate the function of β-catenin, and mutant PS1 may disrupt this regulation. In the present study, we confirm that PS1-WT, as well as mutant PS1-associates with β-catenin, and that mutant PS1 expression decreases the stability and/or enhances the degradation of β- catenin. Most importantly, we correlate β-catenin's destabilization with mutant PS1-associated apoptosis by administering drugs that alter the stability of β-catenin. The application of LiCl and a proteasome inhibitor, N-acetyl-leu-leu-norleucinal (ALLN), increased the stability of cytosolic β- catenin in mutant PS1-expressing cells leading to rescue of these cells from apoptosis. These studies suggest that β-catenin is a key mediator of mutant PS1-associated apoptosis and EAD pathogenesis.
AB - Most early onset cases of familial Alzheimer's disease (FAD) are caused by mutations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to increased β-amyloid formation and induce apoptosis when expressed in vitro. Recently, PS1 has been reported to associate with β-catenin, an armadillo repeat protein. PS1 may regulate the function of β-catenin, and mutant PS1 may disrupt this regulation. In the present study, we confirm that PS1-WT, as well as mutant PS1-associates with β-catenin, and that mutant PS1 expression decreases the stability and/or enhances the degradation of β- catenin. Most importantly, we correlate β-catenin's destabilization with mutant PS1-associated apoptosis by administering drugs that alter the stability of β-catenin. The application of LiCl and a proteasome inhibitor, N-acetyl-leu-leu-norleucinal (ALLN), increased the stability of cytosolic β- catenin in mutant PS1-expressing cells leading to rescue of these cells from apoptosis. These studies suggest that β-catenin is a key mediator of mutant PS1-associated apoptosis and EAD pathogenesis.
KW - Alzheimer's disease
KW - Apoptosis
KW - Presenilin-1
KW - Replication deficient recombinant adenoviral vector
KW - β-Catenin
UR - http://www.scopus.com/inward/record.url?scp=0033588412&partnerID=8YFLogxK
U2 - 10.1097/00001756-199908200-00017
DO - 10.1097/00001756-199908200-00017
M3 - Article
C2 - 10574364
AN - SCOPUS:0033588412
VL - 10
SP - 2527
EP - 2532
JO - NeuroReport
JF - NeuroReport
SN - 0959-4965
IS - 12
ER -