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Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration
Du, Heng Guo, Lan Wu, Xiaoping Sosunov, Alexander A. McKhann, Guy M. Chen, John Xi Yan, Shirley ShiDu
Du, Heng
Guo, Lan
Wu, Xiaoping
Sosunov, Alexander A.
McKhann, Guy M.
Chen, John Xi
Yan, Shirley ShiDu
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Abstract
The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cyclophilin D (CypD), an integral part of mitochondrial permeability transition pore (mPTP), is involved in amyloid beta (Aβ)-instigated mitochondrial dysfunction. Blockade of CypD prevents Aβ-induced mitochondrial malfunction and the consequent cognitive impairments. Here, we showed the elimination of reactive oxygen species (ROS) by antioxidants probucol or superoxide dismutase (SOD)/catalase blocks Aβ-mediated inactivation of protein kinase A (PKA)/cAMP regulatory-element-binding (CREB) signal transduction pathway and loss of synapse, suggesting the detrimental effects of oxidative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-induced ROS. Consequently, CypD-deficient neurons are resistant to Aβ-disrupted PKA/CREB signaling by increased PKA activity, phosphorylation of PKA catalytic subunit (PKA C), and CREB. In parallel, lack of CypD protects neurons from Aβ-induced loss of synapses and synaptic dysfunction. Furthermore, compared to the mAPP mice, CypD-deficient mAPP mice reveal less inactivation of PKA–CREB activity and increased synaptic density, attenuate abnormalities in dendritic spine maturation, and improve spontaneous synaptic activity. These findings provide new insights into a mechanism in the crosstalk between the CypD-dependent mitochondrial oxidative stress and signaling cascade, leading to synaptic injury, functioning through the PKA/CREB signal transduction pathway.
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Date
16-05-16
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Elsevier
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Keywords
Alzheimer's disease, Amyloid beta, Mitochondrial permeability transition, Synaptic alteration, PKA/CREB signaling, Oxidative stress
Citation
Du, Heng, Lan Guo, Xiaoping Wu, Alexander A. Sosunov, Guy M. Mckhann, John Xi Chen, and Shirley Shidu Yan. "Cyclophilin D Deficiency Rescues Aβ-impaired PKA/CREB Signaling and Alleviates Synaptic Degeneration." Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease 1842.12 (2014): 2517-527.