Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration
dc.contributor.author | Du, Heng | |
dc.contributor.author | Guo, Lan | |
dc.contributor.author | Wu, Xiaoping | |
dc.contributor.author | Sosunov, Alexander A. | |
dc.contributor.author | McKhann, Guy M. | |
dc.contributor.author | Chen, John Xi | |
dc.contributor.author | Yan, Shirley ShiDu | |
dc.date.accessioned | 2017-02-01T20:29:05Z | |
dc.date.available | 2017-02-01T20:29:05Z | |
dc.date.issued | 16-05-16 | |
dc.identifier.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. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/22717 | |
dc.description.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. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | 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. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
dc.subject | Alzheimer's disease | en_US |
dc.subject | Amyloid beta | en_US |
dc.subject | Mitochondrial permeability transition | en_US |
dc.subject | Synaptic alteration | en_US |
dc.subject | PKA/CREB signaling | en_US |
dc.subject | Oxidative stress | en_US |
dc.title | Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Yan, Shirley ShiDu | |
kusw.kudepartment | Pharmacology & Toxicology | en_US |
dc.identifier.doi | 10.1016/j.bbadis.2013.03.004 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: 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.