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Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration
- Source :
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842:2517-2527
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
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.
- Subjects :
- Patch-Clamp Techniques
Dendritic spine
medicine.disease_cause
Synaptic Transmission
Antioxidants
Amyloid beta-Protein Precursor
Cyclophilins
chemistry.chemical_compound
PKA/CREB signaling
0302 clinical medicine
Cyclic AMP Response Element-Binding Protein
Cells, Cultured
Mitochondrial permeability transition
Mice, Knockout
Neurons
0303 health sciences
biology
MPTP
Alzheimer's disease
Catalase
Mitochondria
Molecular Medicine
Signal transduction
Cyclophilin D
Signal Transduction
medicine.medical_specialty
Amyloid beta
Immunoblotting
Mice, Transgenic
CREB
Article
03 medical and health sciences
Internal medicine
medicine
Animals
Protein kinase A
Molecular Biology
030304 developmental biology
Synaptic alteration
Amyloid beta-Peptides
Superoxide Dismutase
Cyclic AMP-Dependent Protein Kinases
Oxidative Stress
Probucol
Endocrinology
Mitochondrial permeability transition pore
chemistry
biology.protein
Reactive Oxygen Species
030217 neurology & neurosurgery
Oxidative stress
Subjects
Details
- ISSN :
- 09254439
- Volume :
- 1842
- Database :
- OpenAIRE
- Journal :
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Accession number :
- edsair.doi.dedup.....a216cc7470e98d4ab784f5ba44628de2