title: Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer's neurons.
abstract: Normal axonal mitochondrial transport and function is essential for the maintenance of synaptic function. Abnormal mitochondrial motility and mitochondrial dysfunction within axons are critical for amyloid β (Aβ)-induced synaptic stress and the loss of synapses relevant to the pathogenesis of Alzheimer's disease (AD). However, the mechanisms controlling axonal mitochondrial function and transport alterations in AD remain elusive. Here, we report an unexplored role of cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (mPTP) in Aβ-impaired axonal mitochondrial trafficking. Depletion of CypD significantly protects axonal mitochondrial motility and dynamics from Aβ toxicity as shown by increased axonal mitochondrial density and distribution and improved bidirectional transport of axonal mitochondria. Notably, blockade of mPTP by genetic deletion of CypD suppresses Aβ-mediated activation of the p38 mitogen-activated protein kinase signaling pathway, reverses axonal mitochondrial abnormalities, improves synaptic function, and attenuates loss of synapse, suggesting a role of CypD-dependent signaling in Aβ-induced alterations in axonal mitochondrial trafficking. The potential mechanisms of the protective effects of lacking CypD on Aβ-induced abnormal mitochondrial transport in axon are increased axonal calcium buffer capability, diminished reactive oxygen species (ROS), and suppressing downstream signal transduction P38 activation. These findings provide new insights into CypD-dependent mitochondrial mPTP and signaling on mitochondrial trafficking in axons and synaptic degeneration in an environment enriched for Aβ.
authors: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors: Lan
authors: L
authors: Guo
authors: Heng
authors: H
authors: Du
authors: Shiqiang
authors: S
authors: Yan
authors: Xiaoping
authors: X
authors: Wu
authors: Guy M
authors: GM
authors: McKhann
authors: John Xi
authors: JX
authors: Chen
authors: Shirley ShiDu
authors: SS
authors: Yan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010446:Peptide Fragments / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D021983:Cyclophilins
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