Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy

Abstract

Hypoxia is a profound stressor of the central nervous system implicated in numerous neurodegenerative diseases. While it is increasingly evident that the early effects of hypoxia cause impairment at the level of the axon, the precise mechanisms through which hypoxia compromises axonal structure and function remain unclear. However, links between hypoxia-induced axonopathic disease and the amyloid cascade, as well as the upregulation of amyloid precursor protein (APP) and amyloid beta (Aβ) by hypoxic stress, give rise to the hypothesis that proteolytic cleavage of APP into Aβ may be specifically responsible for axonopathy under conditions of hypoxia. The goal of this dissertation was thus to understand dependence of hypoxia-induced axonal morphological and functional impairment on APP cleavage and the production of Aβ. I have developed a model of hypoxia-induced axonopathy in retinal explants. Using this model, I have experimentally addressed the core hypothesis that APP cleavage, and in particular the formation of Aβ, is necessary and sufficient to mediate morphological and functional axonopathy caused by hypoxia. I have found that there is a dissociation between the mechanisms responsible for hypoxia-induced morphological and functional impairment of the axon in the explanted retina, with the former being dependent on APP-to-Aβ processing and the latter likely being dependent on cleavage of a non-APP substrate by the enzyme BACE1. These findings shed light on mechanisms of hypoxia-induced axonopathy.