Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration Journal Article


Authors: Du, H.; Guo, L.; Wu, X.; Sosunov, A. A.; McKhann, G. M.; Chen, J. X.; Yan, S. S.
Article Title: Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration
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.
Keywords: oxidative stress; alzheimer's disease; mitochondrial permeability transition; amyloid beta; pka/creb signaling; synaptic alteration
Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Volume: 1842
Issue: 12
ISSN: 0925-4439
Publisher: Elsevier B.V.  
Date Published: 2014-12-01
Start Page: 2517
End Page: 2527
Language: English
DOI: 10.1016/j.bbadis.2013.03.004
PROVIDER: scopus
PMCID: PMC3868643
PUBMED: 23507145
DOI/URL:
Notes: Export Date: 2 January 2015 -- Source: Scopus
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  1. Xi Chen
    31 Chen