Determining If Calcium Levels Are Linked To Loss Of Mental Abilities
Testing For Calcium Dysregulation In A New AD Model
Summary
One hypothesis, put forth by several investigators, is that dysregulation of intracellular calcium is an early or central cause of at least some of the symptoms of Alzheimer's disease. In the experiments outlined in this proposal we will determine if the misregulation of intracellular calcium levels is linked to the age of onset of cognitive deficits that we observe in a new Drosophila (fruit fly) model for Alzheimer's disease that is based on loss of presenilin activity.
Details
One way that people get Alzheimer's disease is a by having mutations in the presenilin gene. We have made a fruit fly model of Alzheimer's that has a mutant form of presenilin. Because of their short life-spans and well characterized genome, fruit flies are often used by biologist to study genetics. Interestingly we have found that as these mutant flies age they suffer from a loss of learning and memory, much like Alzheimer's patients. Previous studies suggest that mutation of the presenilin gene results in higher levels of calcium in cells and this might be the cause of some of the symptoms of Alzheimer's disease. We have found that if we treat our Alzheimer's model flies with drugs that should reduce the levels of calcium in cells, we can prevent the loss of learning and memory that occurs with aging in these flies. Our research will look at two items:: if, in fact, calcium levels are higher in the cells of our fly model and if the drug treatments that prevent the loss of learning and memory also bring the calcium levels back to normal. If we can show this, our results will indicate that drug treatments that can reduce calcium levels in cells should be explored as a possible treatment for Alzheimer's disease.
Research Updates
We have developed a new Drosophila (fruit fly) model for Alzheimer's disease (AD) that is based on haplo-insufficiency for the Drosophila presenilin (psn) gene. Haplo-insufficiency 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).
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).
Publications
McBride SM, Choi CH, Schoenfeld BP, Bell AJ, Liebelt DA, Ferreiro D, Choi RJ, Hinchey P, Kollaros M, Terlizzi AM, Ferrick NJ, Koenigsberg E, Rudominer RL, Sumida A, Chiorean S, Siwicki KK, Nguyen HT, Fortini ME, McDonald TV, Jongens T. (2010) Pharmacological and Genetic Reversal of Age-Dependent Cognitive Deficits Attributable to Decreased presenilin Function. Journal of Neuroscience 14;30(28):9510-22. 
First published on: April 14, 2009
Last modified on: March 18, 2011