The Effects of Young Blood Plasma Transfusions on Older hTau Mice Modeling Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder affecting nearly six million individuals in the United States alone. The hallmarks of AD include declines in spatial and episodic memory as well as the build-up of amyloid plaques and tau tangles. This dissertation studied the behavioral and biochemical effects of young plasma transfusions on Alzheimer’s disease mice. Four-month-old rTg4510 h-Tau P301/CaMKII and wildtype mice received seven (150 microliter) plasma or saline transfusions, taken from young 2-month wildtype mice, via intravenous tail injections over three weeks. One week after the completion of the transfusions, the mice were evaluated in Morris Water Maze (MWM) paradigm to measure spatial memory, nest building to measure activities of daily living and Circadian Activity to assess their sleep wake cycles. After completion of the behavioral tasks, the mice transfused at 4-months were sacrificed, and brain tissue was evaluated using Western Blot to examine the amount of tau and phosphorylated tau in the brains as well as thioflavin-S staining to examine the quantity and size of tangles in the brain. In addition, rTg4510 h-Tau P301/CaMKII and wildtype mice were also transfused at 2-months old with seven (150 microliter) saline or plasma transfusions and underwent behavioral testing in the MWM and nest building. The brains of the mice transfused at 2-months were not analyzed as a part of this dissertation. In the mice transfused at 4-months-old, Morris Water Maze data showed a significant effect of genotype across the days a significant effect of plasma. However, the 24-hour probe showed that the AD mice transfused with plasma found the platform significantly faster than the AD mice transfused with saline. It was found that the AD mice transfused with plasma built significantly better nests than the AD mice transfused with saline. There were no significant findings on Circadian Activity. Additionally, Western Blot analysis showed that there was a significant decrease in hyperphosphorylated tau protein in the mice that received plasma transfusions compared to those receiving saline, but no significant differences in total tau between the animals. Thioflavin-S staining showed that mice transfused with plasma had significantly fewer tangles in the CA3 and dentate gyrus of the hippocampus than mice transfused with plasma compared to those transfused with saline. In the mice transfused at 2-months-old, there were no significant differences across the days in Morris water maze. In contrast, nesting showed that AD mice transfused with plasma built significantly better nests than those that received saline. These findings indicate that early plasma transfusions are important in decreasing the amount of phosphorylated tau and tangles in the AD brain and rescuing some behavioral effects. This study provides support for plasma transfusions as a possible treatment for tau pathology found in AD.