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Transcript
Modifiers of Amyloid-beta Toxicity in Alzheimer’s Disease Mayida Azhar Department of Genetics Alzheimer’s disease and Dementia, 2014 Is there an interaction between two pools of Aβ? We secrete Aβ peptides from the neurons of fly brain and study toxicity Secreted Aβ is toxic in Drosophila SSP Ab Crowther 2005 Crowther et et al, al, 2005 Secreted Aβ is toxic in Drosophila Reduced Longevity Wild type Aβ expressing Locomotor deficit 12 Wild type Velocity 10 Aβ expressing 8 6 4 2 0 3 5 8 10 12 15 day 17 19 22 24 26 Plaque like deposits in the brain 0.1 mm Stanislav Ott, 2013 Without SSP, Aβ is expressed in cytoplasm Ab ...but Cytoplasmic Aβ is non-toxic Percent survival Wild type Aβ expressing day No plaque like deposits Stanislav StanislavOtt, Ott,2013 2013 Median Survival (days) What happens if we co-express these constructs? Stanislav StanislavOtt, Ott,2013 2013 Increase in plaque deposition Stanislav Ott, 2013 Which pathways are facilitating this synergy? % increase in median survival An example……CG1824 siRNA RNAi screen outcome 4 Genes 13 Genes Conclusion • There is a synergistic relationship between extracellular and Cytoplasmic Aβ • Gene knockdown at interface of the cells, modifies Aβ toxcity. • We are trying to replicate this effect in mammalian cells and study the pathways involved Many thanks to… Stanislav Ott, Kofan Chen, Jung Yeon, Elenora Pi & Damian Crowther