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Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells.
J Neurochem. 2006 Sep; 98(5):1610-8.JN

Abstract

Early onset familial Alzheimer's disease (FAD) is linked to autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2) genes. These are critical mediators of total amyloid beta-peptide (Abeta) production, inducing cell death through uncertain mechanisms. Tauroursodeoxycholic acid (TUDCA) modulates exogenous Abeta-induced apoptosis by interfering with E2F-1/p53/Bax. Here, we used mouse neuroblastoma cells that express either wild-type APP, APP with the Swedish mutation (APPswe), or double-mutated human APP and PS1 (APPswe/DeltaE9), all exhibiting increased Abeta production and aggregation. Cell viability was decreased in APPswe and APPswe/DeltaE9 but was partially reversed by z-VAD.fmk. Nuclear fragmentation and caspase 2, 6 and 8 activation were also readily detected. TUDCA reduced nuclear fragmentation as well as caspase 2 and 6, but not caspase 8 activities. p53 activity, and Bcl-2 and Bax changes, were also modulated by TUDCA. Overexpression of p53, but not mutant p53, in wild-type and mutant neuroblastoma cells was sufficient to induce apoptosis, which, in turn, was reduced by TUDCA. In addition, inhibition of the phosphatidylinositide 3'-OH kinase pathway reduced TUDCA protection against p53-induced apoptosis. In conclusion, FAD mutations are associated with the activation of classical apoptotic pathways. TUDCA reduces p53-induced apoptosis and modulates expression of Bcl-2 family.

Authors+Show Affiliations

Centro de Patogénese Molecular, Faculty of Pharmacy, University of Lisbon, Portugal.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16923170

Citation

Ramalho, Rita M., et al. "Tauroursodeoxycholic Acid Modulates P53-mediated Apoptosis in Alzheimer's Disease Mutant Neuroblastoma Cells." Journal of Neurochemistry, vol. 98, no. 5, 2006, pp. 1610-8.
Ramalho RM, Borralho PM, Castro RE, et al. Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells. J Neurochem. 2006;98(5):1610-8.
Ramalho, R. M., Borralho, P. M., Castro, R. E., Solá, S., Steer, C. J., & Rodrigues, C. M. (2006). Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells. Journal of Neurochemistry, 98(5), 1610-8.
Ramalho RM, et al. Tauroursodeoxycholic Acid Modulates P53-mediated Apoptosis in Alzheimer's Disease Mutant Neuroblastoma Cells. J Neurochem. 2006;98(5):1610-8. PubMed PMID: 16923170.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells. AU - Ramalho,Rita M, AU - Borralho,Pedro M, AU - Castro,Rui E, AU - Solá,Susana, AU - Steer,Clifford J, AU - Rodrigues,Cecília M P, PY - 2006/8/23/pubmed PY - 2006/10/4/medline PY - 2006/8/23/entrez SP - 1610 EP - 8 JF - Journal of neurochemistry JO - J Neurochem VL - 98 IS - 5 N2 - Early onset familial Alzheimer's disease (FAD) is linked to autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2) genes. These are critical mediators of total amyloid beta-peptide (Abeta) production, inducing cell death through uncertain mechanisms. Tauroursodeoxycholic acid (TUDCA) modulates exogenous Abeta-induced apoptosis by interfering with E2F-1/p53/Bax. Here, we used mouse neuroblastoma cells that express either wild-type APP, APP with the Swedish mutation (APPswe), or double-mutated human APP and PS1 (APPswe/DeltaE9), all exhibiting increased Abeta production and aggregation. Cell viability was decreased in APPswe and APPswe/DeltaE9 but was partially reversed by z-VAD.fmk. Nuclear fragmentation and caspase 2, 6 and 8 activation were also readily detected. TUDCA reduced nuclear fragmentation as well as caspase 2 and 6, but not caspase 8 activities. p53 activity, and Bcl-2 and Bax changes, were also modulated by TUDCA. Overexpression of p53, but not mutant p53, in wild-type and mutant neuroblastoma cells was sufficient to induce apoptosis, which, in turn, was reduced by TUDCA. In addition, inhibition of the phosphatidylinositide 3'-OH kinase pathway reduced TUDCA protection against p53-induced apoptosis. In conclusion, FAD mutations are associated with the activation of classical apoptotic pathways. TUDCA reduces p53-induced apoptosis and modulates expression of Bcl-2 family. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/16923170/Tauroursodeoxycholic_acid_modulates_p53_mediated_apoptosis_in_Alzheimer's_disease_mutant_neuroblastoma_cells_ L2 - https://doi.org/10.1111/j.1471-4159.2006.04007.x DB - PRIME DP - Unbound Medicine ER -