Decreased uptake and binding of11C-nicotine in brain of Alzheimer patients as visualized by positron emission tomography

Nordberg, Agneta; Hartvig, Per; Lilja, Anders; Viitanen, Matti; Amberla, Kaarina; Lundqvist, Hans; Andersson, Yvonne; Ulin, Johan; Winblad, Bengt; Långström, Bengt

doi:10.1007/bf02257652

Cited by 136 publications

(57 citation statements)

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“…Typically, 1 g of RNA was incubated with 1 unit of DNase I in a 10 l-reaction at room temperature for 15 min, and the DNase I was subsequently inactivated by addition of 1 l of 25 mM EDTA and incubation at 65°C for 10 min. RT was carried out using 0.8 g of DNA-free total RNA and oligo(dT) [12][13][14][15][16][17][18] primer in a 20-l reaction using the Superscript II TM Preamplification system (Invitrogen). At the end of the RT reaction, reverse transcriptase was deactivated by incubation at 75°C for 10 min, and RNAs were removed by adding 1 unit of RNase H followed by incubation at 37°C for 30 min.…”

Section: Rna Preparation and Reverse Transcription (Rt)-pcr-totalmentioning

confidence: 99%

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β-Amyloid Directly Inhibits Human α4β2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells

Wu¹,

Kuo

George

et al. 2004

Journal of Biological Chemistry

106

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Amyloid-␤ (A␤) accumulation and aggregation are thought to contribute to the pathogenesis of Alzheimer's disease (AD). In AD, there is a selective decrease in the numbers of radioligand binding sites corresponding to the most abundant nicotinic acetylcholine receptor (nAChR) subtype, which contains human ␣4 and ␤2 subunits (h␣4␤2-nAChR). However, the relationships between these phenomena are uncertain, and effects of A␤ on h␣4␤2-nAChR function have not been investigated in detail. We first confirmed expression of h␣4 and h␤2 subunits as messenger RNA in transfected, human SH-EP1 cells by reverse transcription-polymerase chain reaction and mRNA fluorescence in situ hybridization analyses. Immunoprecipitation Western analyses confirmed ␣4 and ␤2 subunit protein expression and coassembly. Whole cell current recording demonstrated heterologous expression in SH-EP1-h␣4␤2 cells of functional h␣4␤2-nAChRs with characteristic responses to nicotinic agonists or antagonists. Nicotine-induced whole cell currents were suppressed by A␤ 1-42 in a dosedependent manner. Functional inhibition was selective for A␤ 1-42 compared with the functionally inactive, control peptide A␤ 40 -1 . A␤ 1-42 -mediated inhibition of h␣4␤2-nAChR function was non-competitive, voltage-independent, and use-independent. Pre-loading of cells with guanyl-5-yl thiophosphate failed to prevent A␤ 1-42 -induced inhibition, suggesting that down-regulation of h␣4␤2-nAChR function by A␤ 1-42 is not mediated by nAChR internalization. Sensitivity to A␤ 1-42 antagonism at 1 nM was evident for h␣4␤2-nAChRs, but not for heterologously expressed human ␣7-nAChRs, although both nAChR subtypes were functionally inhibited by 100 nM A␤ 1-42 , with the magnitude of functional block being higher for 100 nM A␤ 1-42 acting on h␣7-nAChRs. These findings suggest that h␣4␤2-nAChRs are sensitive and perhaps pathophysiologically relevant targets for A␤ neurotoxicity in AD.Alzheimer's disease (AD) 1 is a progressive, neurodegenerative disorder manifest as a severe impairment of learning and memory. Pathophysiological hallmarks of AD include extracellular deposits of ␤-amyloid peptide (A␤) in senile plaques, formation of intraneuronal neurofibrillary tangles, and cholinergic neuron death (1). Although the precise mechanisms of AD pathogenesis are only partially understood, it is now widely accepted that the accumulation and aggregation of A␤ 1-42 plays a key role in the disease (2). Evidence has indicated an interaction between A␤ and the cholinergic system (3). For example, very low concentrations (pico to nanomolar) of A␤ can directly induce cholinergic hypofunction (4 -6). It has been reported that solubilized A␤ inhibits several steps of acetylcholine synthesis and release (4, 7), inhibits cholinergic enzyme activity (6), impairs cholinergic metabolism and neurotransmission (8 -10), and depresses hippocampal synaptic function (11).Recent evidence suggests possible roles for nicotinic acetylcholine receptors (nAChRs) as central targets for A␤-induced neurotoxicity manifest as...

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Section: Rna Preparation and Reverse Transcription (Rt)-pcr-totalmentioning

confidence: 99%

“…First, in the brain of AD patients, there is a marked decrease in the numbers of nAChR radioligand binding sites (12), particularly those that have the highest affinity for nicotine and appear to be the most abundant nAChR subtype in the brain of vertebrates (13)(14)(15)(16). Immunoassays show that these nAChRs contain ␣4 and ␤2 subunits (17,18).…”

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confidence: 99%

β-Amyloid Directly Inhibits Human α4β2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells

Wu¹,

Kuo

George

et al. 2004

Journal of Biological Chemistry

106

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“…Nicotinic acetylcholine receptors have been implicated in the treatment or pathophysiology of several neuropsychiatric disorders including schizophrenia (Freedman et al, 1994(Freedman et al, , 1997, Alzheimer's disease (Nordberg et al, 1989(Nordberg et al, , 1990), Parkinson's disease (Janson et al, 1988;Reavill, 1990;Grandinetii et al, 1994), and Tourette's syndrome (Sandberg et al, 1988(Sandberg et al, , 1989. Currently available neuropsychiatric medications work primarily by inhibiting neurotransmission through postsynaptic receptor antagonism or by inhibiting neurotransmitter reuptake or catabolism (Schatzberg et al, 1995).…”

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confidence: 99%

α-Conotoxin MII Blocks Nicotine-Stimulated Dopamine Release in Rat Striatal Synaptosomes

Kulak¹,

Nguyen²,

Olivera³

et al. 1997

J. Neurosci.

198

190

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Activation of presynaptic nicotinic acetylcholine receptors (nAChRs) can induce the release of neurotransmitters such as dopamine and norepinephrine in the CNS. Accumulating evidence suggests that distinct nAChR subtypes are involved; however, it has been difficult to determine the subunit composition of these receptors, in part because of the lack of a sufficient variety of selective nAChR ligands. We present experimental data that at least two different nAChR complexes are involved in dopamine release, one of which has an ␣3/␤2 subunit interface.The recently discovered peptide ␣-conotoxin MII is a potent and selective inhibitor of rat nAChRs containing an interface formed by ␣3 and ␤2 subunits. We used this peptide to examine nicotine-stimulated release of dopamine from rat striatal synaptosomes and of norepinephrine from hippocampal synaptosomes. MII (100 nM) blocks 34-49% of the nicotinestimulated dopamine release, but not dopamine release evoked by elevated [K ϩ ]. Furthermore, two peptides structurally related to ␣-conotoxin MII, namely ␣-conotoxin MI (selective for ␣1␤1␥␦ nAChRs) and ␣-conotoxin ImI (selective for ␣7-containing nAChRs), have no effect on nicotine-stimulated dopamine release. The results indicate that one third to half of the dopamine release in the striatal preparation is mediated by nAChRs with an ␣3/␤2 subunit interface. In contrast, Յ10% of nicotine-stimulated release of norepinephrine from hippocampal synaptosomes is modulated by nAChRs with ␣3/␤2 subunit interfaces.

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“…A PET imaging study showed lower accumulation of 11 C-nicotine in the brains of Alzheimer disease patients than in age-matched healthy controls, implying the loss of nicotinic receptors in Alzheimer disease (28). PET studies on patients with Alzheimer disease were also effective in finding a direct correlation between 11 C-nicotine levels in the parietal cortex and the results of a clockdrawing test (16).…”

Section: Discussionmentioning

confidence: 88%

Biodistribution and Radiation Dosimetry of ¹¹C-Nicotine from Whole-Body PET Imaging in Humans

et al. 2016

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This study assessed the in vivo distribution of 11 C-nicotine and the absorbed radiation dose from whole-body 11 C-nicotine PET imaging of 11 healthy (5 male and 6 female) subjects. Methods: After an initial CT attenuation scan, 11 C-nicotine was administered via intravenous injection. A dynamic PET scan was acquired for 90 s with the brain in the field of view, followed by a series of 13 whole-body PET scans acquired over a 90-min period. Regions of interest were drawn over organs visible in the reconstructed PET images. Time-activity curves were generated, and the residence times were calculated. The absorbed radiation dose for the whole body was calculated by entering the residence time in OLINDA/EXM 1.0 software to model the equivalent organ dose and the effective dose for a 70-kg man. Results: The mean residence times for 11 C-nicotine in the liver, red marrow, brain, and lungs were 0.048 6 0.010, 0.031 6 0.005, 0.021 6 0.004, and 0.020 6 0.005 h, respectively. The mean effective dose for 11 C-nicotine was 5.44 6 0.67 mSv/MBq. The organs receiving the highest absorbed dose from the 11 C-nicotine injection were the urinary bladder wall (14.68 6 8.70 mSv/MBq), kidneys (9.56 6 2.46 mSv/ MBq), liver (8.94 6 1.67 mSv/MBq), and spleen (9.49 6 3.89 mSv/ MBq). The renal and hepatobiliary systems were the major clearance and excretion routes for radioactivity. Conclusion: The estimated radiation dose from 11 C-nicotine administration is relatively modest and would allow for multiple PET examinations on the same subject.Key Words: 11 C nicotine; radiation absorbed dose; PET dosimetry; whole-body PET imaging J Nucl Med 2017; 58: 473-478 DOI: 10.2967/jnumed.116.180059 The rate of smoking by adults has decreased substantially in the United States since the hallmark 1964 U.S. Surgeon General's report. Nonetheless, 40 million Americans still smoke regularly, and approximately 400,000 people die each year from illnesses directly associated with smoking (1). Although the various components of tobacco cause different effects, nicotine has been identified as one of the primary chemicals responsible for tobacco addiction in humans (2,3). More recently, there has been a steady rise in the use of newly developed nicotine delivery devices (such as e-cigarettes) to replace cigarettes, and their use has now surpassed that of any other tobacco product, especially among highschool students (4). There is growing concern among the scientific, medical, and regulatory communities over the deleterious impact of nicotine consumption on human health. Aside from the reinforcing action, nicotine perpetuates the smoking habit in humans through the aversive consequences of nicotine withdrawal, a negative reinforcement phenomenon (5-7). Neuronal nicotinic acetylcholine receptors have been identified as one of the primary sites of action in the brain for the elicitation of reinforcing effects, dependency, and withdrawal expressions during cessation of smoking (8)(9)(10)(11)(12). PET imaging is highly useful for studying the impact of smoking ...

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Decreased uptake and binding of11C-nicotine in brain of Alzheimer patients as visualized by positron emission tomography

Cited by 136 publications

References 35 publications

β-Amyloid Directly Inhibits Human α4β2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells

β-Amyloid Directly Inhibits Human α4β2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells

α-Conotoxin MII Blocks Nicotine-Stimulated Dopamine Release in Rat Striatal Synaptosomes

Biodistribution and Radiation Dosimetry of ¹¹C-Nicotine from Whole-Body PET Imaging in Humans

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Decreased uptake and binding of11C-nicotine in brain of Alzheimer patients as visualized by positron emission tomography

Cited by 136 publications

References 35 publications

β-Amyloid Directly Inhibits Human α4β2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells

β-Amyloid Directly Inhibits Human α4β2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells

α-Conotoxin MII Blocks Nicotine-Stimulated Dopamine Release in Rat Striatal Synaptosomes

Biodistribution and Radiation Dosimetry of 11C-Nicotine from Whole-Body PET Imaging in Humans

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Biodistribution and Radiation Dosimetry of ¹¹C-Nicotine from Whole-Body PET Imaging in Humans