Tauroursodeoxycholic acid prevents amyloid-β peptide-induced neuronal death via a phosphatidylinositol 3-kinase-dependent signaling pathway

Susana Solá, Rui E. Castro, Pedro A. Laires, Clifford J. Steer, Cecília M.P. Rodrigues

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, modulates cell death by interrupting classic pathways of apoptosis. Amyloid-β (Aβ) 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 Aβ-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 Aβ 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′-OH kinase (Pl3K) pathway with wortmannin did not markedly affect Aβ-induced cell death, suggesting that this signaling pathway is not crucial for Aβ-mediated toxicity. Notably, co-incubation with TUDCA significantly modulated each of the Aβ-induced apoptotic events. Moreover, wortmannin decreased TUDCA protection against Aβ-induced apoptosis, reduced Akt phosphorylation, and increased Bax translocation to mitochondria. Together, these findings indicate that Aβ-induced apoptosis of cortical neurons proceeds through a Bax mitochondrial pathway. Further, the Pl3K signaling cascade plays a role in regulating the anti-apoptotic effects of TUDCA.

Original languageEnglish (US)
Pages (from-to)226-234
Number of pages9
JournalMolecular Medicine
Volume9
Issue number9-12
DOIs
StatePublished - 2003

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