Du, HengGuo, LanWu, XiaopingSosunov, Alexander A.McKhann, Guy M.Chen, John XiYan, Shirley ShiDu2017-02-012017-02-0116-05-16Du, 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.https://hdl.handle.net/1808/22717The 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.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.http://creativecommons.org/licenses/by-nc-nd/3.0/Alzheimer's diseaseAmyloid betaMitochondrial permeability transitionSynaptic alterationPKA/CREB signalingOxidative stressCyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degenerationArticle10.1016/j.bbadis.2013.03.004openAccess