Testing For Calcium Dysregulation In A New AD Model

Progress Updates

We have developed a new Drosophila (fruit fly) model for Alzheimer's disease (AD) that is based on haploinsufficiency for the Drosophila presenilin (psn) gene. Haploinsufficiency means that of the two copies for any one gene in an organism, one of them is inactive and the remaining gene can't produce enough protein for normal activity, so it causes a disease state. In this case, problems with the psn gene cause early-onset familial Alzheimer's disease. In studying this fruit fly model of AD (that we call psn-het flies), we have found age dependent deficits in learning and memory that can be prevented by treatment with mGluR protein antagonists, or by genetic reduction of the inositol-trisphosphate receptor calcium release channel (InsP3R) pathway. One of our most significant findings in this reporting period has revealed that we observe no nerve cell loss in the time frame in which the cognitive deficits are observed. These results are consistent with published literature that indicates that synaptic loss (meaning, loss of the communication between nerve cells) is a better predictor of cognitive loss than cell loss.

To further verify that our results are occurring due to a problem in synaptic dysfunction versus cell loss, we have tested the effect of treating the psn-het flies starting at day 30 (when deficits in learning and memory are observed) up until day 45 and re-testing their learning and memory. What we have found is that we can reverse the loss of learning and memory, restoring it to normal levels, as compared to control flies. This result further supports the idea that the cognitive deficits we are detecting in our model are more likely due to a defect in signaling, such as problems with the calcium (Ca2+) release, as we have proposed. These results have been included in a manuscript that has recently been published (McBride et al.,2010).