1013V Poster Online - Virtual Posters
Wednesday April 06, 4:00 PM - 7:00 PM

Authors:
Sher Li Tan ^1,2; Robert Richards ¹; Tim Sargeant ²; Louise O'Keefe ^1,2

Affiliations:
1) The University of Adelaide, Adelaide, South Australia, Australia; 2) South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

Keywords:
w. genetic modifiers of disease; l. endosomes

Introduction: Alzheimer’s disease (AD) is the most common form of dementia, which affects memory, behaviour and daily functioning of affected patients with its pathological characteristics consisting of amyloid-beta (Aβ) plaques and phosphorylated tau accumulation in the brain. The mechanisms underlying the disease remain unknown and no effective treatments are available to prevent disease progression. Although the genetic contribution in AD patients is not fully understood, genome-wide association studies (GWAS) have identified several loci associated with increased AD risk in genes within the endolysosomal network (ELN). However, the fundamental mechanism of AD disease progression regarding ELN is not well defined. Therefore, this project aims to identify and characterise the contribution of individual ELN genes to neuronal dysfunction in a Drosophila model for AD.

Method/Approach: Co-expression of full length amyloid precursor protein and beta-site APP cleaving enzyme (APP+BACE) has been investigated in Drosophila to determine whether flies are able to model symptoms observed in AD patients. The advantage of this APP+BACE model is that it will ensure correct spatial localisation of APP and its proteolytic fragments within the ELN. Phenotypes generated form the basis for genetic modification analyses of individual ELN genes.

Result: Our findings show that co-expression of APP+BACE causes retinal degeneration in the adult eye and this can be modified by altered expression of Rab5 or Rab7 ELN genes. In addition, neuronal expression of APP+BACE in flies has led to progressive loss of motor functions, behavioural problems, and a reduced lifespan.

Conclusion: Using this system, we can characterise the genetic and molecular contribution of individual ELN genes to APP+BACE toxicity.