Isoflurane exposure during mid-adulthood attenuates age-related spatial memory impairment in APP/PS1 transgenic mice

Abstract

Many in vitro findings suggest that isoflurane exposure might accelerate the process of Alzheimer Disease (AD); however, no behavioral evidence exists to support this theory. In the present study, we hypothesized that exposure of APP/PS1 transgenic mice to isoflurane during mid-adulthood, which is the pre-symptomatic phase of amyloid beta (Abeta) deposition, would alter the progression of AD. Seven-month-old Tg(APPswe,PSEN1dE9)85Dbo/J transgenic mice and their wild-type littermates were exposed to 1.1% isoflurane for 2 hours per day for 5 days. Learning and memory ability was tested 48 hours and 5 months following isoflurane exposure using the Morris Water Maze and Y maze, respectively. Abeta deposition and oligomers in the hippocampus were measured by immunohistochemistry or Elisa 5 months following isoflurane exposure. We found that the performance of both the transgenic and wild-type mice in the Morris Water Maze significantly improved 48 hours following isoflurane exposure. The transgenic mice made significantly fewer discrimination errors in the Y maze following isoflurane exposure, and no differences were found between wild-type littermates 5 months following isoflurane exposure. For the transgenic mice, the Abeta plaque and oligomers in the hippocampus was significantly decreased in the 5 months following isoflurane exposure. In summary, repeated isoflurane exposure during the pre-symptomatic phase not only improved spatial memory in both the APP/PS1 transgenic and wild-type mice shortly after the exposure but also prevented age-related decline in learning and memory and attenuated the Abeta plaque and oligomers in the hippocampus of transgenic mice.

Figure 1. The Morris Water Maze was performed 48 hours after the final isoflurane exposure.

The isoflurane exposure, but not the presence of the transgene, significantly affected the escape latency, swimming pathway and the swimming time in the target quadrant during probe test. The average swimming speeds were similar among groups. A: The mean latency to find the platform was shorter following the isoflurane exposure for both the transgenic and wild-type mice. *: p<0.05 on the third day compared with transgenic and wild-type mice not exposed to isoflurane. B: The mean pathway to find the platform was shorter following the isoflurane exposure for both the transgenic and wild-type mice. *: p<0.05 on the third day compared with transgenic and wild-type mice not exposed to isoflurane. C: The swimming speed was similar among the four groups. D: During the probe trial, wild-type mice exposed to isoflurane spent more time in the target quadrant following the isoflurane exposure. The X-axis (days) corresponds to the testing paradigm in Figure 1 (days 8–11). (Ad-iso, n = 20; Ad-con, n = 20; Wt-iso, n = 16; Wt-con, n = 13).

Figure 2. The Y maze was performed five months following the isoflurane exposure.

A: The number of learning trails to reach the final criterion. No difference was found among the groups. B: Avoidance errors. No difference was found among the groups. C: Discrimination errors. The mice in the Ad-iso group made significantly fewer discrimination errors than the mice in the Ad-con group. No difference was found between the two wild-type groups. *: p<0.05 compared with the Ad-con group. D: No difference in the foot shock voltage was found among the groups. (Ad-iso, n = 20; Ad-con, n = 20; Wt-iso, n = 16; Wt-con, n = 13).

Figure 3. Abeta plaques and oligomers in the hippocampus.

Following the isoflurane exposure during mid-adulthood, compared to the Ad-con group (A), the Abeta plaque was significantly decreased in the Ad-iso group (B). Statistical analysis of the percent area of the Abeta plaques in the hippocampus and dentate gyrus(C). Compared to the Ad-con group, the Abeta oligomer was significantly decreased in the Ad-iso group (D) 5 months following isoflurane exposure. (n = 5).

Figure 4. A two-hour isoflurane exposure did not significantly affect blood pressure and heart rate.

Animals maintained stable heart rates (A) and blood pressure (B). (n = 5).

Figure 5. Schematic timeline of the experimental paradigm.