Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: Protective role of tauroursodeoxycholate

Mitochondria have been implicated in the cytotoxicity of amyloid beta -pept ide (A beta), which accumulates as senile plaques in the brain of Alzheimer 's disease patients. Tauroursodeoxycholate (TUDC) modulates cell death, in part, by preventing mitochondrial membrane perturbation. Using electron par amagnetic resonance spectroscopy analysis of isolated mitochondria, we test ed the hypothesis that A beta acts locally in mitochondrial membranes to in duce oxidative injury, leading to increased membrane permeability and subse quent release of caspase-activating factors. Further, we intended to determ ine the role of TUDC at preventing A beta -induced mitochondrial membrane d ysfunction, The results demonstrate oxidative injury of mitochondrial membr anes during exposure to A beta and reveal profound structural changes, incl uding modified membrane lipid polarity and disrupted protein mobility. Cyto chrome c is released from the intermembrane space of mitochondria as a cons equence of increased membrane permeability, TUDC, but not cyclosporine A, a lmost completely abrogated A beta -induced perturbation of mitochondrial me mbrane structure. We conclude that A beta directly induces cytochrome c rel ease from mitochondria through a mechanism that is accompanied by profound effects on mitochondrial membrane redox status, lipid polarity, and protein order. TUDC can directly suppress A beta -induced disruption of the mitoch ondrial membrane structure, suggesting a neuroprotective role for this bile salt, (C) 2001 Academic Press.