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.
|Original language||English (US)|
|Number of pages||6|
|State||Published - Aug 20 1999|
- Alzheimer's disease
- Replication deficient recombinant adenoviral vector
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