Aims

People with Down Syndrome (DS) carry an extra copy of human chromosome 21 (Hsa21), including amyloid precursor protein (APP). Duplication of APP alone has been shown to be sufficient to cause early-onset Alzheimer’s Disease (AD) (Sleegers et al., 2006). However, the contribution of other Hsa21 gene duplications to AD risk is not yet understood. Using a Trisomic mouse model (Tc1) that lacks functional APP, Wiseman et al., demonstrated that the triplication of Hsa21 genes other than APP increases the risk of AD pathology (Wiseman et al., 2018).

We aim to identify which other Hsa21 genes, when expressed at higher levels in people with DS, modify Aß accumulation or cognitive decline.

Methods

To identify genes that modify Aß aggregation, we are using the fruit fly Drosophila melanogaster as a screening tool. We will be using two main readouts of increased Aß accumulation. Firstly, a negative geotaxis assay to assess neuromotor function of Aß expressing flies that overexpress one of the Hsa21 homologues. Secondly, Aß_1-42 levels will be quantified by ELISA. Genes that are found to have an effect on Aß aggregation in the fly brain will be examined in human post-mortem brain tissue, to determine if they are overexpressed in people who had DS compared with euploid individuals.

Results

We are currently undertaking the screen of 42 genes. The data presented will be that of the current state of the screen.

Conclusions

Conclusions will be drawn once the screen has been completed.