Journal
NEUROBIOLOGY OF DISEASE
Volume 77, Issue -, Pages 94-105Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2015.02.027
Keywords
Axonopathy; Axonal degeneration; Axonal transport; Amyloid precursor protein; Amyloid beta; Retinal explant
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Funding
- National Science Foundation Graduate Research Fellowship [DGE-1106401]
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Axonopathy is a common and early phase in neurodegenerative and traumatic CNS diseases. Recent work suggests that amyloid beta (A beta) 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 A beta is a necessary step in structural compromise of retinal ganglion cell (RGC) axons induced by the disease-relevant stressor hypoxia. However, identical blockade of A beta production was not sufficient to protect axons from associated hypoxia-induced reduction in axonal transport. Thus, A beta 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. (C) 2015 Elsevier Inc. All rights reserved.
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