Abstract
393
Objectives: A reduction in nicotinic α4β2 receptors has been reported cortex (CTX), hippocampus (HP) and thalamus (TH) in Alzheimer’s disease (AD). Using the PET tracer, 18F-nifene, our goals are to evaluate: 1. α4β2 receptors in transgenic mouse models of AD of β-amyloid plaques (Tg2576) and models of β-amyloid plaques and neurofibrillary tangles (3xTg, triple-transgenic); 2. Binding at different ages of the 3xTg transgenic mice. Results may provide evidence on the role of α4β2 receptor function in transgenic AD models. Methods: 18F-Nifene was prepared as described in earlier studies. Two AD transgenic mice models were used: Tg2576 (15 mo) and 3xTg triple transgenic (1, 2, 15 and 18 mo old). Whole brain sagittal sections (10 μm thick) were obtained from the Tg mice and wild-type (WT) mice of comparable age. Brain sections were treated with 18F-nifene with concentrations ∼3µCi/cc. The sections were incubated for 60 min at 37 oC, washed (2×2 min cold buffer, water rinse), air dried and exposed to phosphor screens. Nonspecific binding was measured in the presence of 300µM of nicotine. Binding was determined by autoradiograms analyzed by OptiQuant Image Analysis Software. Adjacent mice brain sections were also immunostained with Aβ42 antibody and thioflavin to confirm presence of β-amyloid plaques. Results: Majority of the old transgenic mice brains displayed a significant decrease in total binding of 18F-nifene. Ratios of TH to cerebellum (CB) in the 15mo-18mo 3xTg and Tg2576 models showed >90% loss of 18F-nifene compared to the 18 mo WT (Th/Cb= 15 in WT; 1 in Tg mice, 15-18 mo). Similar losses occurred in other brain regions (HP, CTX). Presence of β-amyloid plaques in these mice sections (HP, CTX and other brain regions) was confirmed with immunostaining and thioflavin. The younger transgenic models (1 and 2 mo) did not show a signifcant loss in 18F-nifene binding in the TH. Conclusions: Results indicate significant loss of 18F-nifene binding in the older mice of two Tg models. The loss may be due to the blockade/conformational change of α4β2 receptors by β-amyloid plaques/tangles in the transgenic mice models. Use of 18F-nifrolene, an α4β2 antagonist, in Tg mice is underway to evaluate differences between agonist and antagonist binding.
- Society of Nuclear Medicine, Inc.