Light Dependent Endolysosomal Defects in a Photoreceptor Model of Alzheimer's Disease

Alzheimer’s disease (AD) is a neurodegenerative disease which is the 6th leading cause of death in the US. AD pathology is thought to be linked to the accumulation and aggregation of toxic proteins, amyloid-beta and tau. AD development and neurodegeneration is proposed to be caused by the toxic effects of these protein accumulations, specifically amyloid-beta, as postulated by the amyloid-cascade hypothesis. To study the relationship between amyloid-beta and overall neuronal health, a study was carried out using an amyloid-expressing fruit fly photoreceptor model. Using this model, toxicity of amyloid in a stressed lysosomal system induced by light, an established lysosomal stressor to the fly eye, was assessed. Exposure to light increases neurodegeneration in amyloid-expressing photoreceptors. Furthermore, light exposure normally induces endocytosis and lysosomal degradation of rhodopsin, but rhodopsin accumulates in intracellular puncta in amyloid-expressing photoreceptors exposed to light. Subsequently, it was postulated that the endolysosomal defects of these photoreceptors are exacerbated when exposed to light, due to bulk endocytosis of rhodopsin. To test this theory, the formation of rhodopsin was blocked by raising flies without vitamin A. Inhibiting rhodopsin formation dramatically rescued light-dependent photoreceptor degeneration. Experiments are underway to block the firing of action potentials in amyloid-expressing photoreceptors by co-expressing an inward-rectifying potassium channel. This will differentiate between degeneration caused by rhodopsin endocytosis and that caused by neuronal activity. Additionally, the endolysosomal defect observed in amyloid-expressing photoreceptors is being characterized by means of colocalization studies. To identify the organelles containing rhodopsin accumulations, immunofluorescent staining for endosomes, lysosomes, and autophagosomes will be carried out. Findings thus far indicate that the presence of amyloid-beta does exacerbate endolysosomal dysfunction and neurodegeneration. By characterizing the exact defect in this pathway involved in rhodopsin accumulation, information gleaned will shed light on the underlying flawed mechanisms in AD pathology. Such insights will inform a more detailed understand of AD development and progression. This will in turn allow medical researchers to identify and or advance novel therapeutics targeting these defects, providing a much needed solution to a tragic disease with few effective therapies available to treat victims.