Abnormal [ 18 F]NIFENE binding in transgenic 5xFAD mouse model of Alzheimer's disease: In vivo PET/CT imaging studies of α4β2* nicotinic acetylcholinergic receptors and in vitro correlations with Aβ plaques¶.

Since cholinergic dysfunction has been implicated in Alzheimer's disease (AD), the effects of Aβ plaques on nicotinic acetylcholine receptors (nAChRs) α4β2* subtype, was studied using the transgenic 5xFAD mouse model of AD. Using the PET radiotracer [ 18 F]nifene for α4β2* nAChRs, in vitro autoradiography and in vivo PET/CT studies in 5xFAD mice were carried out and compared with wild-type (C57BL/6) mice. Ratios of [ 18 F]nifene binding versus cerebellum (CB) in 5xFAD mice brains for thalamus (TH) = 17, hippocampus-subiculum (HP-SUB) = 7, frontal cortex (FC) = 5.5 and striatum (ST) = 4.7. [ 125 I]IBETA and immunohistochemistry (IHC) in 5xFAD brain slices confirmed Aβ plaques. Nicotine and acetylcholine displaced [ 18 F]nifene in 5xFAD mice (IC 50 nicotine = 31-73 nM; ACh = 38-83 nM) and C57BL/6 (IC 50 nicotine = 16-18 nM; ACh = 34-55 nM). Average [ 18 F]nifene SUVR (CB as reference) in 5xFAD FC = 3.04 and in C57BL/6 FC = 1.92 (p = 0.001) while TH difference between 5xFAD (SUVR = 2.58) and C57BL/6 (SUVR = 2.38) was not significant. Nicotine-induced dissociation half life (t 1/2 ) of [ 18 F]nifene for TH were 37 mins for 5xFAD and 26 mins for C57BL/6 and for FC 77 mins for C57BL/6 while no dissociation of [ 18 F]nifene occurred in the FC of 5xFAD mice. Coregistration of [ 18 F]nifene PET with MR suggested the medial prefrontal cortex (mPFC) and anterior cingulate (AC) regions exhibited uptake in 5xFAD mice. Ex vivo [ 18 F]nifene and in vitro [ 125 I]IBETA Aβ plaque autoradiography after in vivo PET/CT scan of 5xFAD mouse brain were moderately correlated (r 2 = 0.68). In conclusion, 5xFAD mice showed increased non-displaceable [ 18 F]nifene binding in mPFC. This article is protected by copyright. All rights reserved.