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TUDCA, a Bile Acid, Attenuates Amyloid Precursor Protein Processing and Amyloid-β Deposition in APP/PS1 Mice

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) peptide in the hippocampus and frontal cortex of the brain, leading to progressive cognitive decline. The endogenous bile acid tauroursodeoxycholic acid (TUDCA) is a strong neuroprotective agent in several experimental models of disease, including neuronal exposure to Aβ. Nevertheless, the therapeutic role of TUDCA in AD pathology has not yet been ascertained. Here we report that feeding APP/PS1 double-transgenic mice with diet containing 0.4 % TUDCA for 6 months reduced accumulation of Aβ deposits in the brain, markedly ameliorating memory deficits. This was accompanied by reduced glial activation and neuronal integrity loss in TUDCA-fed APP/PS1 mice compared to untreated APP/PS1 mice. Furthermore, TUDCA regulated lipid-metabolism mediators involved in Aβ production and accumulation in the brains of transgenic mice. Overall amyloidogenic APP processing was reduced with TUDCA treatment, in association with, but not limited to, modulation of γ-secretase activity. Consequently, a significant decrease in Aβ1–40 and Aβ1–42 levels was observed in both hippocampus and frontal cortex of TUDCA-treated APP/PS1 mice, suggesting that chronic feeding of TUDCA interferes with Aβ production, possibly through the regulation of lipid-metabolism mediators associated with APP processing. These results highlight TUDCA as a potential therapeutic strategy for the prevention and treatment of AD.

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Acknowledgments

The authors thank Prodotti Chimici e Alimentari S.p.A. (Basaluzzo, Italy) for the supply of TUDCA. APP/PS1 mice were kindly donated by Bart De Strooper. We also wish to thank Véronique Hendrickx for assistance in genotyping the mice. This work was supported by grant PTDC/SAU-NMC/117877/2010 from Fundação para a Ciência e a Tecnologia (FCT), Portugal. AFN and JDA were recipients of postdoctoral fellowships (SFRH/BPD/34603/2007 and SFRH/BPD/47376/2008, respectively); RJV and MBF were recipients of Ph.D. fellowships (SFRH/BD/30467/2006 and SFRH/BD/43959/2008, respectively) from FCT. RDH and ACL were funded by 7FP grant MEMOSAD and the federal science fund FWO-Vlaanderen (grant number G.0327.08).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon, 1649-003, Portugal

    Ana F. Nunes, Joana D. Amaral, Maria B. Fonseca, Ricardo J. S. Viana & Cecília M. P. Rodrigues

  2. Laboratory of Biological Psychology, University of Leuven, Leuven, Belgium

    Adrian C. Lo, Zsuzsanna Callaerts-Vegh & Rudi D’Hooge

  3. Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    Cecília M. P. Rodrigues

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  1. Ana F. Nunes
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  2. Joana D. Amaral
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  4. Maria B. Fonseca
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  5. Ricardo J. S. Viana
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Correspondence to Cecília M. P. Rodrigues.

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Nunes, A.F., Amaral, J.D., Lo, A.C. et al. TUDCA, a Bile Acid, Attenuates Amyloid Precursor Protein Processing and Amyloid-β Deposition in APP/PS1 Mice. Mol Neurobiol 45, 440–454 (2012). https://doi.org/10.1007/s12035-012-8256-y

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