| First Author | Du H | Year | 2014 |
| Journal | Biochim Biophys Acta | Volume | 1842 |
| Issue | 12 Pt A | Pages | 2517-27 |
| PubMed ID | 23507145 | Mgi Jnum | J:230483 |
| Mgi Id | MGI:5760129 | Doi | 10.1016/j.bbadis.2013.03.004 |
| Citation | Du H, et al. (2014) Cyclophilin D deficiency rescues Abeta-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim Biophys Acta 1842(12 Pt A):2517-27 |
| abstractText | 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 (Abeta)-instigated mitochondrial dysfunction. Blockade of CypD prevents Abeta-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 Abeta-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 Abeta-induced ROS. Consequently, CypD-deficient neurons are resistant to Abeta-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 Abeta-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. |
