The role of beta-catenin stability in mutant PS1-associated apoptosis.
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 beta-amyloid formation and induce apoptosis when expressed in vitro. Recently, PS1 has been reported to associate with beta-catenin, an armadillo repeat protein. PS1 may regulate the function of beta-catenin, and mutant PS1 may disrupt this regulation. In the present study, we confirm that PS1-WT, as well as mutant PS1, associates with beta-catenin, and that mutant PS1 expression decreases the stability and/or enhances the degradation of beta-catenin. Most importantly, we correlate beta-catenin's destabilization with mutant PS1-associated apoptosis by administering drugs that alter the stability of beta-catenin. The application of LiCl and a proteasome inhibitor, N-acetyl-leu-leu-norleucinal (ALLN), increased the stability of cytosolic beta-catenin in mutant PS1-expressing cells leading to rescue of these cells from apoptosis. These studies suggest that beta-catenin is a key mediator of mutant PS1-associated apoptosis and FAD pathogenesis.
Weihl
C C
CC
Committee on Neurobiology, University of Chicago, IL 60637, USA.
Miller
R J
RJ
Roos
R P
RP
D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015820:Cadherins / Q000502:physiology*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D016716:PC12 Cells; D053764:Presenilin-1; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D015534:Trans-Activators; D014779:Virus Replication; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D015534:Trans-Activators; D051176:beta Catenin