Amyloid β-Peptide Disrupts Mitochondrial Membrane Lipid and Protein Structure: Protective Role of Tauroursodeoxycholate

Abstract

Mitochondria have been implicated in the cytotoxicity of amyloid β-peptide (Aβ), 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 paramagnetic resonance spectroscopy analysis of isolated mitochondria, we tested the hypothesis that Aβ acts locally in mitochondrial membranes to induce oxidative injury, leading to increased membrane permeability and subsequent release of caspase-activating factors. Further, we intended to determine the role of TUDC at preventing Aβ-induced mitochondrial membrane dysfunction. The results demonstrate oxidative injury of mitochondrial membranes during exposure to Aβ and reveal profound structural changes, including modified membrane lipid polarity and disrupted protein mobility. Cytochrome c is released from the intermembrane space of mitochondria as a consequence of increased membrane permeability. TUDC, but not cyclosporine A, almost completely abrogated Aβ-induced perturbation of mitochondrial membrane structure. We conclude that Aβ directly induces cytochrome c release 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 Aβ-induced disruption of the mitochondrial membrane structure, suggesting a neuroprotective role for this bile salt.