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APPLICATION OF DOUBLE MR IMAGING TO DETECT AMYLOID OLIGOMERS IN THE BRAIN OF APP/PS1 TRANSGENIC MODEL MICE

      Background

      We have developed two types of potential imaging agents using 19F-MRI: 19F-containing styrylbenzoxazole derivative (Shiga-X22) and curcumin derivative (Shiga-Y5). Shiga-Y5 detects both Aβ oligomers and Aβ aggregates, while Shiga-X22 only detects Aβ aggregates. Thus, the Shiga-Y5 images subtracted by Shiga-X22 may reflect the images of Aβ oligomers. In this study, we applied double MR probe-imaging to detect amyloid oligomers in the brain of APPswe/PS1dE9 double transgenic model mice.

      Methods

      All experimental procedures were approved by the Animal Care and Use Committee of our University. Six APPswe/PS1dE9 double transgenic mice at age of 20-month-old were used. We simultaneously injected Shiga-Y5 and Shiga-X22 at a dose of 200 mg/kg into the tail vein of three mice. At 3-h after the injection, 19F chemical shift imaging was obtained using a 7-tesla MR scanner. Another three mice were killed by overdose of sodium pentobarbital and we removed the brain. Then, the concentrations of Aβ oligomers were measured by enzyme-linked immunosorbent assay (ELISA).

      Results

      The 19F MR signal of Shiga-Y5 appeared mainly in the olfactory bulb, the subcortical area, and the cerebellum. In contrast, the 19F MR signal of Shiga-X22 displayed predominantly in the olfactory bulb, the cortex, and the cerebellum. Then, we produced a subtracted image by subtracting 19F MR images of Shiga-X22 from that of Shiga-Y5. 19F MR signal in the subtracted image was located in the subcortical area. ELISA measurement showed that Aβ oligomers uniformly distributed in the brain except for the brainstem, and there is no specific region showing the accumulation of Aβ oligomers. In contrast, the level of insoluble Aβ was significantly less in the subcortical area where the concentration of insoluble Aβ was relatively low. The imbalance between relative high level of Aβ oligomers and the less level of insoluble Aβ in the subcortical area may contribute to intense 19F MR signal in the subtracted image.

      Conclusions

      We employed double probe MR images using Shiga-Y5 and SHiga-X22 to detct Aβ oligomers in the brain of AD model mouse.