Abstract
394
Objectives: Reduced dopamine D2/D3 receptors has been reported in postmortem Alzheimer's disease (AD). Using 18F-fallypride (18F-FAL), our goals are: 1.Evaluate 18F-FAL binding in transgenic (Tg) mouse models of AD that develop β-amyloid(Aβ) plaques (Tg2576), or both Aβ plaques and neurofibrillary tangles (3xTg, triple-transgenic); 2.Compare 18F-FAL at different ages of Tg mice; and 3.Evaluate effect of the anti-amyloidogenic compound curcumin (CUR) on 18F-FAL. These findings will support the use of 18F-FAL in evaluating loss and recovery of D2/D3 receptors in Tg AD models. Methods: 18F-FAL was prepared as described in earlier studies. Sagittal brain sections (10 µm) were obtained from Tg2576 (15 mo), 3xTg (1, 2, 15 and 18 mo old) models and wild-type (WT) mice of comparable age and treated with ∼1.5 µCi/cc of 18F-FAL. Sections were incubated for 60 min at 37oC, then washed (2×2 min cold buffer,water), air dried and exposed to phosphor screens. Nonspecific binding was measured with 10µM haloperidol. Sections were incubated with 18F-FAL at 37oC for 1, 2 and 4 hr in presence and absence of 6 µM CUR. Binding of 18F-FAL were determined by autroradiograms and analyzed by OptiQuant Image Analysis Software. Adjacent sections were immunostained with an anti-Aβ antibody and thioflavin to confirm Aβ plaques. Results: Old Tg mice brains (15m, 18m) displayed a significant decrease in 18F-FAL binding. Ratios of striatum (str) to cerebellum (cb) in the 15m 3xTg model showed 81.8% loss of 18F-FAL binding compared to the 18m WT. The 18m 3xTg and Tg2576 showed 89.7% and 90.9% loss, respectively. The presence of Aβ plaques in these sections (hippocampus, cortex) was confirmed with immunostaining and thioflavin fluorescence. In the younger Tg models (1m, 2m) loss in binding was ∼15-20%. CUR caused an increase in 18F-FAL binding. After 1h exposure to CUR, Tg2576 str/cb = 13.4 (no CUR) and str/cb = 21.4 (with CUR). Effect of CUR at 2 and 4h was small due to a loss in the integrity of the brain sections. Thus, 1h CUR treatment recovered ∼10-15% of 18F-FAL binding in the 15m Tg2576 when compared to WT mice. Conclusions: These data suggest loss of 18F-FAL binding to dopamine receptors in Tg mouse models of AD. Anti-amyloidogenic compounds such as CUR, which reduce Aβ plaque load, may help in the recovery of receptor function.
- Society of Nuclear Medicine, Inc.