Abnormal [¹⁸F]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

Abstract

Since cholinergic dysfunction has been implicated in Alzheimer's disease (AD), the effects of Aβ plaques on nicotinic acetylcholine receptors (nAChRs) α4β2* subtype were studied using the transgenic 5xFAD mouse model of AD. Using the PET radiotracer [18F]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 [18F]nifene binding in brain regions versus cerebellum (CB) in 5xFAD mice brains were for thalamus (TH) = 17, hippocampus‐subiculum = 7, frontal cortex (FC) = 5.5, and striatum = 4.7. [125I]IBETA and immunohistochemistry (IHC) in 5xFAD brain slices confirmed Aβ plaques. Nicotine and acetylcholine displaced [18F]nifene in 5xFAD mice (IC50 nicotine = 31–73 nM; ACh = 38–83 nM) and C57BL/6 (IC50 nicotine = 16–18 nM; ACh = 34–55 nM). Average [18F]nifene SUVR (CB as reference) in 5xFAD mice was significantly higher in FC = 3.04 compared to C57BL/6 mice FC = 1.92 (p = .001), whereas TH difference between 5xFAD mice (SUVR = 2.58) and C57BL/6 mice (SUVR = 2.38) was not significant. Nicotine‐induced dissociation half life (t1/2) of [18F]nifene for TH were 37 min for 5xFAD mice and 26 min for C57BL/6 mice. Dissociation half life for FC in C57BL/6 mice was 77 min , while no dissociation of [18F]nifene occurred in the medial prefrontal cortex (mFC) of 5xFAD mice. Coregistration of [18F]nifene PET with MR suggested that the mPFC, and anterior cingulate (AC) regions exhibited high uptake in 5xFAD mice compared to C57BL/6 mice. Ex vivo [18F]nifene and in vitro [125I]IBETA Aβ plaque autoradiography after in vivo PET/CT scan of 5xFAD mouse brain were moderately correlated (r2 = 0.68). In conclusion, 5xFAD mice showed increased non‐displaceable [18F]nifene binding in mPFC.

Glutamate’s Effects on the N-Methyl-D-Aspartate (NMDA) Receptor Ion Channel in Alzheimer’s Disease Brain: Challenges for PET Radiotracer Development for Imaging the NMDA Ion Channel

“…A strategy to assess potential radiotracers for the NMDA ion channel, as outlined in Figure 10 , has to take this “neurotransmitter-induced” radiotracer binding factor into account. Small animal models that may possess altered ion channel activity (due to elevated glutamate and glycine levels) will be important to assess the feasibility of radiotracers to measure in vivo open NMDA receptor ion channels [ 54 , 55 , 56 ]. It is very likely that this factor of non-availability of open ion-channels resulted in discarding potential radiotracers, which otherwise may have been useful [ 38 ].…”

Comparison of Monoamine Oxidase-A, Aβ Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer’s Disease Brain

“…Gray matter (GM) and WM binding of each radiotracer in the AD and CN subjects were measured, and the GM/WM ratios of the AD and CN subjects were compared for each radiotracer. Using the ratio method is akin to in vivo PET methods, where the standard uptake value (SUV) between the target region is compared to a nonspecific binding reference region as a ratio and expressed as SUVR [ 58 , 59 ]. Group differences of GM/WM ratios between AD and CN subjects were evaluated using t -tests.…”

Synthesis and Evaluation of Compound Targeting α7 and β2 Subunits in Nicotinic Acetylcholinergic Receptor

“…Autoradiography of [ 18 F]nifene in mice and rat brain slices were previously reported [3,12]. Briefly, slides with brain slices were incubated with [ 18 F]nifene in a Tris buffer pH 7.4 (60 mL; 37 kBq/mL) and was added to the chambers and were incubated at 25 • C for 1 h. Nonspecific binding was measured in separate chambers in the presence of 300 µM nicotine.…”

“…Neuronal nicotinic cholinergic receptors (nAChRs) are involved in learning, memory, addiction, and neuropsychatric illnesses [1]. Dysfunction of these receptors has been implicated in numerous human conditions including Alzheimer's disease (AD) [2,3], Parkinson's disease (PD) [4], and others. Several nAChR subtypes are present in the mammalian brain, with heteromeric α4β2 and homomeric α7 subtypes being in larger concentrations than the other subtypes ( [5,6] Figure 1).…”