Inhibition Of Cyclophilin D Rescues Mitochondrial Defects In Alzheimer’s Disease Cybrid Cells

Cyclophilin D (CypD) is a peptidyl prolyl isomerase F that plays a central role in opening the mitochondrial membrane permeability transition pore leading to cell death. It resides in the mitochondrial matrix and associates with the inner mitochondrial membrane. CypD interacts with amyloid beta (Aβ) to exacerbate mitochondrial and neuronal stress and has been linked to Alzheimer’s disease (AD). Here, we report the biological activity of two small-molecμle CypD inhibitors (6A and 6C), which bind strongly to CypD and attenuate mitochondrial and cellular perturbation insulted by Aβ and calcium stress. In vitro surface plasmon resonance studies were used to determine binding affinities for the two compounds.6C shows better binding affinities in this experiment. In the following experiment, both compounds reduced CypD peptidyl prolyl isomerase enzyme activity and antagonized calcium-mediated mitochondrial swelling. However, 6A seems better than 6C in these two experiments, which may be caused by different reaction conditions. More importantly, these compounds also abolished mitochondrial dysfunction in AD cybrid cells as shown by increased mitochondrial membrane potential, cytochrome c oxidase and adenosine-5’-triphosphate levels. These results suggest that these small molecule CypD inhibitors may serve as a potential drug for the prevention and treatment of neurodegenerative disease including Alzheimer’s disease.