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Biochim Biophys Acta. 2014 Dec;1842(12 Pt A):2517-27. doi: 10.1016/j.bbadis.2013.03.004. Epub 2013 Mar 16.

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

Author information

1
Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
2
Department of Neurosurgery, Physicians & Surgeons College of Columbia University, New York, NY 10032, USA.
3
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 1003, USA.
4
Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA. Electronic address: shidu@ku.edu.

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:

Alzheimer's disease; Amyloid beta; Mitochondrial permeability transition; Oxidative stress; PKA/CREB signaling; Synaptic alteration

PMID:
23507145
PMCID:
PMC3868643
DOI:
10.1016/j.bbadis.2013.03.004
[Indexed for MEDLINE]
Free PMC Article

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