Tauroursodeoxycholic acid prevents amyloid-beta peptide-induced neuronal death via a phosphatidylinositol 3-kinase-dependent signaling pathway.
Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, modulates cell death by interrupting classic pathways of apoptosis. Amyloid-beta (Abeta) peptide has been implicated in the pathogenesis of Alzheimer's disease, where a significant loss of neuronal cells is thought to occur by apoptosis. In this study, we explored the cell death pathway and signaling mechanisms involved in Abeta-induced toxicity and further investigated the anti-apoptotic effect(s) of TUDCA. Our data show significant induction of apoptosis in isolated cortical neurons incubated with Abeta peptide. Apoptosis was associated with translocation of pro-apoptotic Bax to the mitochondria, followed by cytochrome c release, caspase activation, and DNA and nuclear fragmentation. In addition, there was almost immediate but weak activation of the serine/threonine protein kinase Akt. Inhibition of the phosphatidylinositide 3 prime-OH kinase (PI3K) pathway with wortmannin did not markedly affect Abeta-induced cell death, suggesting that this signaling pathway is not crucial for Abeta-mediated toxicity. Notably, co-incubation with TUDCA significantly modulated each of the Abeta-induced apoptotic events. Moreover, wortmannin decreased TUDCA protection against Abeta-induced apoptosis, reduced Akt phosphorylation, and increased Bax translocation to mitochondria. Together, these findings indicate that Abeta-induced apoptosis of cortical neurons proceeds through a Bax mitochondrial pathway. Further, the PI3K signaling cascade plays a role in regulating the anti-apoptotic effects of TUDCA.
Solá
Susana
S
Centro de Patogenese Molecular, Faculty of Pharmacy, University of Lisbon, Portugal.
Castro
Rui E
RE
Laires
Pedro A
PA
Steer
Clifford J
CJ
Rodrigues
Cecília M P
CM
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005333:Fetus; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D045304:Cytochromes c; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D013655:Taurochenodeoxycholic Acid; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; C494821:Bad protein, rat; C494828:Bax protein, rat; C074636:amyloid beta-protein (25-35); C031655:ursodoxicoltaurine; C494920:Akt1 protein, rat