The role of beta-catenin stability in mutant PS1-associated apoptosis

• Published in: Neuroreport Vol. 10; no. 12; p. 2527
• Main Authors: Weihl, C C, Miller, R J, Roos, R P
• Format: Journal Article
• Language: English
• Published: England 20.08.1999
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - physiopathology; Animals; Apoptosis - physiology; beta Catenin; Cadherins - physiology; Cell Line; Cytoskeletal Proteins - physiology; Genetic Vectors; Humans; Membrane Proteins - genetics; Mutation; PC12 Cells; Presenilin-1; Rats; Retroviridae - genetics; Trans-Activators; Virus Replication
• ISSN: 0959-4965
• DOI: 10.1097/00001756-199908200-00017

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.