Tauroursodeoxycholic acid prevents E22Q Alzheimer’s Aβ toxicity in human cerebral endothelial cells

Abstract

The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule tauroursodeoxycholic acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.

Bile acids: regulation of apoptosis by ursodeoxycholic acid

“…Moreover, during liver regeneration, increased levels of UDCA were shown to inhibit bile acid- ing Bax translocation ( 105 ). Similar results were obtained in primary human cerebral endothelial cells incubated with the vasculotropic E22Q A ␤ mutant that is associated with hereditary cerebral hemorrhage in amyloidosis Dutch type ( 143 ). Interestingly, TUDCA was not capable of modulating the secondary structure and the fi brillogenic propensities of A ␤ , suggesting dissociation between the capacity to induce apoptosis and the mechanisms of aggregation and fi brillization.…”

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

“…Administration of TUDCA reduced amyloid deposition and prevented the defects in spatial, recognition, and contextual memory in APP/PS1 mice and was shown to prevent Dutch-mutated Aβ-induced apoptosis of cultured cerebral endothelial cells (Viana et al, 2009).…”

Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity

“…Simvastatin effectively blocked the proinflammatory reactions induced by Aβ 1−40 peptide in a human brain endothelial cell line [69]. Tauroursodeoxycholic acid, an antiapoptotic endogenous bile acid inhibited the apoptosis of human brain cerebral endothelial cells triggered by the vasculotropic Aβ 1−40 E22Q mutant peptide [70]. While apolipoprotein-E4 increased, apolipoprotein-E2 decreased the cytotoxic effect of Aβ 1−40 and Aβ 1−42 pepides [71].…”