Nebula/DSCR1 upregulation preserves axonal transport and memory function in a Drosophila model for Alzheimer's disease

2015-03-12The Down syndrome critical region 1 gene (also called regulator of calcineurin and Nebula) is located in the DSCR region of human chromosome 21 and upregulated in post-mortem brains from Down syndrome (DS) and Alzheimer’s disease (AD) patients. Questions remain as to whether elevated expression of DSCR1 is exacerbating disease pathology or delaying degeneration. The goal of this dissertation is to gain insight into the role of DSCR1/Nebula in Alzheimer’s disease. Over the course of my research, I explored the functional interaction between DSCR1/Nebula and the amyloid precursor protein (APP), which is known to cause AD when duplicated or upregulated in DS. I find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration, ameliorates axonal transport defects caused by APP overexpression, and preserves memory function in young flies by regulating phosphatase and kinase activity. ❧ APP upregulation results in the accumulation of pre-synaptic proteins in the axons and increases in calcineurin and glycogen synthase kinase 3 beta (GSK-3β) activity. Live-imaging experiments reveal that nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, these findings imply that correcting calcineurin and GSK-3β can prevent APP-induced pathologies. ❧ I further investigate the effects of DSCR1/Nebula upregulation on amyloid precursor protein-induced learning and memory deficits. I find that while upregulation of nebula alone impairs memory, co-upregulation of APP and nebula can effectively restore APP-induced memory defects, but only in young Drosophila. Nebula/DSCR1 overexpression rescues perturbations in calcineurin and cAMP signaling caused by APP overexpression. Surprisingly, nebula accelerated age-dependent memory impairments, increased reactive oxygen species, and enhanced mitochondrial dysfunction in aged flies. This finding suggests that upregulation of DSCR1 may delay APP-induced memory problems initially but enhances memory decline at a later age. My data further demonstrates that acute upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation; however, chronic upregulation of nebula negatively affects memory. Finally, I present evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport and memory impairments associated with AD