Tauroursodeoxycholic acid prevents E22Q Alzheimer's A beta toxicity in human cerebral endothelial cells

Viana, R. J. S.; Nunes, A. F.; Castro, R. E.; Ramalho, R. M.; Meyerson, J.; Fossati, S.; Ghiso, J.; Rostagno, A.; Rodrigues, C. M. P.

http://hdl.handle.net/10451/21100

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Abstract(s)

The vasculotropic E22Q mutant of the amyloid-beta (A beta) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the A beta E22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by A beta E22Q and wild-type A beta revealed that only A beta E22Q triggered the Bax mitochondrial pathway of apoptosis. A beta E22Q neither matched the fast oligomerization kinetics of A beta 42 nor reached its predominant beta-sheet structure, achieving a modest degree of oligomerization with a secondary structure that remained a mixture of beta and random conformations. The endogenous molecule tauroursodeoxycholic acid (TUDCA) was a strong modulator of A beta E22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of A beta peptides. These data dissociate the pro-apoptotic properties of A beta peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.. - Fundacao para a Ciencia e a Tecnologia (FCT), Lisbon, Portugal [PTDC/BIABCM/67922/2006, BD/30467/2006, BPD/34603/2007, BPD/30257/2006, BPD/40623/2007]; NIH [NS051715, AG10491]; American Heart Association.. - This work was supported by grant PTDC/BIABCM/67922/2006 from Fundacao para a Ciencia e a Tecnologia (FCT), Lisbon, Portugal; NIH grants NS051715 andAG10491; and the American Heart Association. R.J.S.V. is the recipient of a PhD fellowship from FCT, Portugal (BD/30467/2006); A.F.N., R.E.C. and R. M. R. are recipients of postdoctoral fellowships from FCT, Portugal (BPD/34603/2007, BPD/30257/2006 and BPD/40623/2007, respectively).