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.
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Physicians & Surgeons College of Columbia University, New York, NY 10032, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Physicians & Surgeons College of Columbia University, New York, NY 10032, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Sosunov
authors.affiliation: Department of Neurosurgery, Physicians & Surgeons College of Columbia University, New York, NY 10032, USA.
authors.forename: Guy M
authors.initials: GM
authors.lastname: McKhann
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 1003, USA.
authors.forename: John Xi
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA. Electronic address: shidu@ku.edu.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011341:Probucol / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase; D017868:Cyclic AMP-Dependent Protein Kinases; D021983:Cyclophilins; D011341:Probucol
keywords: Alzheimer's disease; Amyloid beta; Mitochondrial permeability transition; Oxidative stress; PKA/CREB signaling; Synaptic alteration