Investigation of the Endolysosomal Network in a Drosophila Model of Alzheimer’s Disease

Abstract

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. This thesis uses the co-expression of human full-length amyloid precursor protein and beta-site APP cleaving enzyme 1 (APP+BACE) as the Drosophila model for AD. This AD model exhibited a rough eye phenotype due to retinal degeneration and could be modified by overexpression of Rab5 or reduction of Rab7 genes. Using transgenic RNAi technology, the candidate genes in the ELN components such as Rbpn5, Nuf, Vps26, Stam, Chmp1, and Babo were identified to be the enhancers of APP+BACE-mediated retinal degeneration. This suggests that ELN components are considered as functionally significant for APP+BACE pathogenesis and represent potential therapeutic targets for AD. Furthermore, the contribution of diet to AD toxicity was examined using this model. This revealed that a low protein to high carbohydrate diet (LPHC) at ratio of P:C=1:16 significantly prolonged the lifespan of APP+BACE flies, suggesting LPHC diet can be beneficial in AD.