The study provides new insights into the mechanism underlying mitochondrial Aβ-mediated and synaptic stress that links to the mitochondrial permeability transition pore (mPTP), an opening that leads to cell death for those with Alzheimer's. Mitochondrial permeability transition pore causes mitochondrial swelling, outer membrane rupture and release of cell death mediators and enhances production of reactive oxygen species (ROS). Cyclophilin D (CypD), a type of enzyme called a prolyl isomerase that is located within the mitochondrial matrix, is an integral part in the formation of the mitochondrial permeability transition pore (mPTP), leading to cell death. Up until now, however, the role of CypD in Alzheimer's disease has not been elucidated.
In this paper, Dr. Yan and colleagues demonstrate that CypD interacts with Aβ peptide within the mitochondria of Alzheimer's disease patients and a transgenic mouse model of Alzheimer's disease. The cortical mitochondria isolated from Alzheimer's disease mice lacking CypD are resistant to Aβ- and Ca2+-induced mitochondria swelling and permeability transition, increase calcium buffering capacity, and attenuate generation of mitochondrial ROS. Furthermore, CypD-deficient neurons protect against Aβ- and oxidative stress-induced cell death. Importantly, deficiency of CycD greatly improved the learning, memory, and synaptic function of an Alzheimer's disease mouse model and alleviated Aβ-mediated reduction of long term potentiation (LTP). Thus, the CypD/Aβ-mediated mitochondrial permeability transition pore directly links to the cellular and synaptic perturbation relevant to the pathogenesis of Alzheimer's disease.
|Contact: Karin Eskenazi|
Columbia University Medical Center