Transcript Secreted Aβ is toxic in Drosophila

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