Differential roles of Aß 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 ß (Aß) 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 Aß is a necessary step in structural compromise of retinal ganglion cell (RGC) axons induced by the disease-relevant stressor hypoxia. However, identical blockade of Aß production was not sufficient to protect axons from associated hypoxia-induced reduction in axonal transport. Thus, Aß 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.