title: Differential roles of Aβ processing in hypoxia-induced axonal damage.
abstract: Axonopathy is a common and early phase in neurodegenerative and traumatic CNS diseases. Recent work suggests that amyloid β (Aβ) produced from amyloid precursor protein (APP) may be a critical downstream mediator of CNS axonopathy in CNS diseases, particularly those associated with hypoxia. We critically tested this hypothesis in an adult retinal explant system that preserves the three-dimensional organization of the retina while permitting direct imaging of two cardinal features of early-stage axonopathy: axonal structural integrity and axonal transport capacity. Using this system, we found via pharmacological inhibition and genetic deletion of APP that production of Aβ is a necessary step in structural compromise of retinal ganglion cell (RGC) axons induced by the disease-relevant stressor hypoxia. However, identical blockade of Aβ production was not sufficient to protect axons from associated hypoxia-induced reduction in axonal transport. Thus, Aβ mediates distinct facets of hypoxia-induced axonopathy and may represent a functionally selective pharmacological target for therapies directed against early-stage axonopathy in CNS diseases.
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC, USA. Electronic address: melissa.christianson@alumni.duke.edu.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Christianson
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001369:Axons / Q000473:pathology*; D002772:Cholera Toxin / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D021621:Imaging, Three-Dimensional; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000166:cytology; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D002772:Cholera Toxin
keywords: Amyloid beta; Amyloid precursor protein; Axonal degeneration; Axonal transport; Axonopathy; Retinal explant