Title of Research Grant

Identification of susceptibility genes for Alzheimer’s Disease in Down Syndrome

Researcher

Ralf S Schmid
Applicant’s Primary Department: Neurobiology

Scientific Summary of Proposed Project

Down Syndrome (DS) is the most common chromosomal condition, resulting from the overexpression of a number of genes due to a third copy of chromosome 21 (chr 21).  Ongoing studies are providing increasingly refined lists of overexpressed genes and their contribution to disease symptoms that include neurodevelopmental defects, resulting in intellectual disability from the time of birth.  However, it is unknown as to which of these genes may contribute to the striking clinical observation that a substantial proportion of DS patients develop Alzheimer’s disease (AD) in their 30s and 40s.  AD is a fatal, progressive neurodegenerative disease that, in contrast, normally occurs only in the elderly of the general population.  In this context, we propose to investigate the genetic and genomic factors that may trigger AD in comparatively young patient with DS. We hypothesize that these genes may be those on chr 21 that are overexpressed due to the trisomy, and propose to evaluate directly the potential of these chr 21 genes to enhance the development of AD pathology in a novel AD neurodegeneration assay we have developed using biolistically transfected rat cortical/hippocampal brain slice explants.  The outcome of this studies will increase our understanding of the biochemical pathways by which DS must pre-dispose for mid-life onset of AD, and will be critical for identifying drug target for specific use in reducing risk for and slowing the progression of AD in DS patients.

Lay Summary of Proposed Project

Becoming elderly is often associated with various forms of dementia, but for people with Down syndrome, the most common chromosomal condition, dementia in the form of Alzheimer’s disease commonly begins in the 30s and 40s, several decades earlier than in the rest of the population. Alzheimer’s disease is a devastating neurodegenerative disorder that drastically decreases life expectancy likely due to the toxic effect of b-amyloid protein accumulation in the brain.  The link between Down syndrome and such young onset of Alzheimer’s disease is poorly understood.

As Down syndrome is caused by inheritance of an additional copy of chromosome 21, we propose to investigate whether certain genes or gene regions on chromosome 21 could be the cause for mid-life onset of Alzheimer’s disease in people with Down syndrome.  We have developed a novel research model system where we can study Alzheimer’s disease in the lab in live rat brain tissues. We use a device called a gene gun to deliver genes from chromosome 21 into this model system and will ask if any of them accelerate and worsen the development of Alzheimer’s disease.

We hope that the outcome of this project will help us to better understand why people with Down syndrome are susceptible to Alzheimer’s disease at such an early age, and to open up new avenues for therapeutic development for this form of Alzheimer’s disease.