Molecular Medicine

, Volume 9, Issue 9–12, pp 226–234 | Cite as

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


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 (PI3K) 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 PI3K signaling cascade plays a role in regulating the anti-apoptotic effects of TUDCA.



The authors thank Paulo Ribeiro for skillful technical assistance. This work was supported by grant POCTI/BCI/44929/2002 from Fundação para a Ciência e a Tecnologia (FCT), Lisbon, Portugal (to CMPR), and PhD fellowships SFRH/BD/4823/2001 and SFRH/BD/12655/2003 (to SS and REC, respectively) from FCT.


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Copyright information

© Feinstein Institute for Medical Research 2003

Authors and Affiliations

  • Susana Solá
    • 1
  • Rui E Castro
    • 1
  • Pedro A Laires
    • 1
  • Clifford J Steer
    • 2
    • 3
  • Cecília M P Rodrigues
    • 1
  1. 1.Centro de Patogénese Molecular, Faculty of PharmacyUniversity of LisbonLisbonPortugal
  2. 2.Department of MedicineUniversity of Minnesota Medical SchoolMinneapolisUSA
  3. 3.Departments of Genetics, Cell Biology, and DevelopmentUniversity of Minnesota Medical SchoolMinneapolisUSA

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