An Analysis of Young Blood Plasma Transfusions in the rtg4510 Mouse Model of Alzheimer’s Disease

Author(s): Jonathan Sanchez

Mentor(s): Jane Flinn, Neutoscience

Abstract

More than five million Americans are impacted by Alzheimer’s Disease. There are currently no known cures for this disease and the current treatments are limited to slowing the progression of the disease. In this study, blood transfusions were performed in 8-month-old transgenic models of Alzheimer’s Disease presenting with tau type pathology. This study fulfills a gap by a previous study only examining the effects of plasma transfusion in an amyloidogenic model of Alzheimer’s Disease. The present study was performed last year and the current analysis explores further effects of plasma transfusions. Our analysis reveals that mice did not experience an improvement in anxiety symptoms associated with Alzheimer’s Disease. The analysis also demonstrates that plasma transfusions worsened performance despite an improvement in pathological condition. These results may help with the future design of experiments looking to explore plasma transfusions as a potential treatment for the disease.

Video Transcript

Hi my name is Jonathan and this semester I conducted an extended analysis on a study performing blood plasma transfusions from young mice to old mice with Alzheimer’s Disease. 

Prior research has indicated that plasma transfusion from young mice may improve cognitive outcomes in older mice. 

This project was an extension of a prior study that used young blood plasma transfusions for the treatment of Alzheimer’s Disease. These studies have indicated that blood plasma transfusions have a benefit in improving memory deficits associated with Alzheimer’s, in addition to restoring some function of molecular pathways involved in neuronal transmission at synapses. 

This project aims to fulfill a gap not covered in the JAMA Neurology published study which  only used the amyloid expressing transgenic model. 

Alzheimer’s Disease has two hallmark pathological features: amyloid and tau. These proteins are naturally found in the brain and become improperly cleaved during Alzheimer’s. They then aggregate around neuronal synapses and impair function leading to neuronal death. This is what induces cognitive decline. 

Our study looks at the impacts of plasma transfusion in the rtg4510 model which expresses tau type pathology. 

Over the course of one week 8-month-old rtg4510 mice models and wild type controls received 8 injections of plasma or placebo saline via the tail vein. Plasma was collected from the blood of 2-3 month old young wildtype mice. 

Behavioral testing was conducted after injections. These methods included Morris Water Maze (to test spatial memory) , circadian rhythm, nesting and burrowing (to test activities of daily living), and open field (to test anxiety and locomotion) . 

Remarkably, mice that received plasma injections did not have any improvement in behavioral assays compared to those that were treated with a placebo. So, my extended analysis looked into thigmotaxicity, a measure of anxiety during Morris water maze, which revealed an effect by genotype. Thigmotaxicity is measured as the time spent on the outside portion of the pool which indicates anxiety. Further analysis shows that the Alzheimer’s model did not experience any improvement in anxiety. Overall, diseased mice experienced more anxiety, however plasma transfusions did not improve their condition. In fact, plasma treated mice performed worse than the placebo as noted in the graph on the right. 

During Morris water maze, mice must swim to a platform.  A shorter time to platform indicates better learning ability. Our analysis demonstrated that plasma treated mice did not experience any benefits and also performed worse than their placebo counterparts. 

To give further detail on the effects on anxiety, open field test was used in addition to the Morris water maze. Again, time spent on the outer portion of the box indicates more anxiety. In the original experiment, distance is used as a control for locomotion. It is important to note that the rtg4510 model is hyperactive because of genetic manipulation and not a disease feature. Tau expressing mice experienced more anxiety than wildtype as expected, however, an analysis of  the open field test was performed where the effect of injection type did not make a difference and the difference between diseased and non-diseased mice was not as significant in comparison to the Morris water maze. 

These images were produced using immunofluorescent staining technique by using fluorescent anti-bodies to tag hyperphosphorylated tau. This is where our shock on the behavioral results derives from. Although behavioral testing did not show much improvement in cognitive impairments, the histological analysis that was previously performed, showed significant reduction in the presence of tau proteins. This was especially noted in the cortex. We attribute the lack of improvement in our behavioral analysis to the treatment being performed too late. Neuronal repair mechanisms would not be able to recover the damage that had already been done. 

These results give more information to the scientific community on potential treatments for Alzheimer’s Disease. Clinical studies using plasma are already being performed and this experiment will give better information to the design of future experiments involving human plasma transfusions. Thank you for listening and I am happy to take questions.

3 replies on “An Analysis of Young Blood Plasma Transfusions in the rtg4510 Mouse Model of Alzheimer’s Disease”

Nice presentation, Jonathan. I am fascinated by the idea that there is improvement in the brain that is not reflected in the behavior. You hypothesize that the lack of behavioral recovery is because of the injections being given when too much damage had already been done. What is the next step to test this hypothesis? Also, is it possible that with more time, mice could recover more function?

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