Tauroursodeoxycholic acid prevents E22Q Alzheimer's Abeta toxicity in human cerebral endothelial cells.
The vasculotropic E22Q mutant of the amyloid-beta (Abeta) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the AbetaE22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by AbetaE22Q and wild-type Abeta revealed that only AbetaE22Q triggered the Bax mitochondrial pathway of apoptosis. AbetaE22Q neither matched the fast oligomerization kinetics of Abeta42 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 AbetaE22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of Abeta peptides. These data dissociate the pro-apoptotic properties of Abeta peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.
Viana
R J S
RJ
iMed.UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Nunes
A F
AF
Castro
R E
RE
Ramalho
R M
RM
Meyerson
J
J
Fossati
S
S
Ghiso
J
J
Rostagno
A
A
Rodrigues
C M P
CM
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D055806:Microvessels / Q000166:cytology; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D021381:Protein Transport; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016229:Amyloid beta-Peptides; D051028:bcl-2-Associated X Protein; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D045304:Cytochromes c