Transfusion with Blood Plasma from Young Mice Affects rTg4510 Transgenic Tau Mice Modeling of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is characterized by the buildup of plaques and tangles in the brain. Tangles are formed when the stabilizing protein, tau, becomes hyperphosphorylated and clumps together. There are limited treatments for AD; therefore, the exploration of new treatments is warranted. Previous research showed that plasma transfusion from young donor mice improved spatial memory and increased synaptic proteins in old transgenic APP/PS1 mice, suggesting a remediation of memory and synaptic function. In the current study, plasma was transfused from 2-3-month-old young wildtype mice (WT) to 8-month-old rTg4510 mice expressing human tau (Tau). One week after the transfusions, behavior and tau pathology were examined. We found that Tau mice injected with plasma had lower expression of phosphorylated tau (ptau) in the brain, accompanied by fewer tau tangles in the cortex and CA1 region of the hippocampus and smaller tau tangles in the cortex, when compared to Tau mice injected with saline. Despite no improvement in behavior, the decreased level of ptau and tangles open the door to future studies involving plasma transfusions.

Keywords: Alzheimer’s disease; blood plasma; blood transfusion; neurofibrillary tangles.

Figure 1

Timeline of behavioral test.

Figure 2

(A) Number of tau tangles in the brain of Tau mice. Tau mice injected with saline have more tangles in the somatosensory cortex (p = 0.032) and CA1 region of the hippocampus (p = 0.044) compared to the Tau mice injected with plasma. (* = p < 0.05). (B) Size of tangles in the brain of Tau mice. Tau mice injected with saline have larger tangles in the somatosensory cortex (p = 0.001) compared to the Tau mice injected with plasma. (*** = p < 0.001).

Figure 3

Thioflavin-S tau tangle microscope images at 20× magnification: the green levels were set to 1.26, and the exposure time of 0.28 s was consistent for all images. The images were captured from similar brain areas to show comparison between plasma-injected mice and saline-injected mice. (A–E) images are from Tau mice given saline injections. (F–J) images are from Tau mice given plasma injections. (K,L) are higher-magnification images to show the pathology of tau tangles from the prefrontal cortex of Tau mice.

Figure 4

(A) Tau5 Western blot analysis. Tau mice, regardless of injection, have a greater expression of tau than WT mice. (*** = p < 0.001). Tau 5 ~50kD; loading control GAPDH ~35kD. (B) pSer396 Western blot analysis. Overall, Tau mice have a higher expression of phosphorylated tau than WT mice (p = 0.001). Additionally, Tau mice injected with saline have a higher expression of phosphorylated tau than Tau mice injected with plasma (p = 0.047). (* = p < 0.05, *** = p < 0.001). pSer396 ~52kD; loading control β-actin ~42kD (double bands indicate actin degradation). (C) pThr231 Western blot analysis. Tau mice injected with plasma have a lower expression of phosphorylated tau than Tau mice injected with saline (F(1,6) = 5.548, p = 0.057). (+ = p < 0.05). pThr231 ~79 kD; loading control GAPDH ~35kD.

Figure 5

GFAP Western blot analysis. Tau mice have a higher expression of astrocyte activity than WT mice. (** = p < 0.01). GFAP-α ~55kD; GFAP-ΔEx7 ~48 kD; GFAP-Δ164 between ~48 kD and ~35 kD; loading control GAPDH ~35 kD.

Figure 6

(A) MWM latency to find platform. Results show that Tau mice have a significantly longer latency to reach the platform compared to WT mice, regardless of injection (p < 0.001). There is a significant effect of day (p < 0.001); the mice reached the platform faster on day 6 than on days 1 (p < 0.001), 2 (p = 0.019), and 5 (p < 0.015). (*** = p < 0.001). (B) MWM platform crosses. Tau mice make significantly fewer platform crosses compared to WT mice regardless of injection (p < 0.001). Day 7 was a probe day and was, thus, separated from the other days. (*** = p < 0.001). (C) MWM Thigmotaxicity. Tau mice spend significantly more time in the outer 10% of the pool compared to WT mice. There is a significant effect of day (p < 0.001); the mice spent significantly less time near the walls on day 7 than on days 2 and 6 (p < 0.0001). (*** = p < 0.001).