Alzheimer's Disease: Genes Impacting Ab and Tau Neurotoxicity
A major goal of this research project is to identify potential therapeutic targets capable of suppressing neuronal degeneration caused by the toxic effects of the two main proteins implicated in Alzheimer's Disease (AD): the b-amyloid (ab42) and tau.
A second goal is to identify genetic risk factors, as well as the genetic pathways and molecular mechanisms underlying neuronal degeneration in ad. To this end we have generated a drosophila model of ad by targeted expression of the human ab42 and wild-type tau proteins to Drosophila neurons. Expression of either ab42 or tau alone leads to progressive neuronal degeneration evident in Drosophila eye and/or brain neurons. We find that expression of both proteins simultaneously has super-additive effects leading to more severe neuronal and behavioral phenotypes.
We are using the Drosophila AD model to identify genes that, when altered, can ameliorate the toxic effects of ab42 and tau. We are also interested in recovering genes that aggravate ab42 and tau toxicity. Both types of modifier genes are important because suppressors may lead to therapeutic targets, enhancers may lead to risk factors, and both may identify molecular mechanisms of neuronal degeneration. The Drosophila model system is very well suited for this type of genetic analysis because it is feasible to test both the loss of function and the gain of function of most genes with respect to their effect on ab42 and tau neuronal toxicity. This type of analysis is impractical with mouse models because of time and cost considerations, and because of number of genetic variants available
Relevance of the project to IDDRC mission:
Alzheimer's Disease leads to severe cognitive impairments. Identifying molecular pathogenic mechanisms and genetic modifiers relevant to Alzheimer's will facilitate the development of therapeutic approaches.