Replacing Alzheimer's disease (AD) - Down syndrome (DS) mice with fly models

World-wide ~ 6 million people have Down syndrome (DS), and are at significantly greater risk of developing Alzheimer’s disease (AD) than the general population. By the age of 40, almost all people with DS will develop AD pathology, namely amyloid plaques and neurofibrillary tangles within their brain. The vast majority of people who have DS will go on to develop early onset dementia (AD-DS), with a mean age of onset of ~ 57 years. DS is caused by an extra copy of human chromosome 21 (Hsa21), which encodes 231 genes. One of these genes (APP) codes for a protein that is cleaved to form the amyloid-beta (Aβ) that accumulates in plaques during AD. How the other genes on Hsa21 affect disease is not yet understood. We have recently shown using mouse models that a gene(s) on Hsa21, other than APP, exacerbates the accumulation of Aβ (Wiseman et al Brain 2018). This suggests that the increase in AD rates in DS individuals is not purely driven by an extra copy of APP.

We have gone on to show that the gene(s) responsible for the exacerbation of Aβ accumulation is found on a region of Hsa21 that contains 39 genes. We now want to determine which of these gene(s) is responsible for the increase in pathology and to develop alternatives to existing mouse models for future research into AD-DS mechanisms. Identification of the causal gene will provide new insight into disease development which may also have implications for disease progression in the general population. The identification of novel pathways in this project will also provide potential new targets for the development of disease therapies.

Dementia is a growing concern for society, as the incidence of this devastating and incurable group of diseases continues to grow. Dementia research has been identified by government as a priority area because of the huge societal impact caused. Developing alternative model systems to replace conventional mouse models of dementia thus has significant potential to reduce UK mouse research use.