Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Nordberg, Agneta; Lundqvist, Hans; Hartvig, Per; Andersson, Jan; Johansson, Monika; Hellström‐Lindahl, Ewa; Långström, Bengt

doi:10.1159/000106611

Cited by 97 publications

(55 citation statements)

References 25 publications

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“…Several studies have corroborated postmortem reports of reductions in nAChRs in Alzheimer's disease using PET [28,29] or SPECT [30], which correlate with impaired cognitive function [16]. To our knowledge, no studies have yet investigated in vivo healthy aging effects on high affinity nAChRs.…”

Section: Introductionmentioning

confidence: 82%

Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

Mitsis

Cosgrove

Staley

et al. 2009

Neurobiology of Aging

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Human postmortem studies have reported decreases with age in high affinity nicotine binding in brain. We investigated the effect of age on β 2 -containing nicotinic acetylcholine receptor (β 2 -nAChR) availability in eight brain regions of living human subjects using the ligand [ 123 I]5-IA-85380 ([ 123 I]5-IA) and single photon emission computed tomography (SPECT). Healthy, nonsmokers (N=47) ranging in age from 18-85 were administered [ 123 I]5-IA using a bolus plus constant infusion paradigm and imaged 6-8 h later under equilibrium conditions. The effect of age on regional β 2 -nAChR availability (V T , regional brain activity/free plasma parent, a measure proportional to the binding potential) was analyzed using linear regression and Pearson's correlation (r). Age and regional β 2 -nAChR availability were inversely correlated in seven of the eight brain regions analyzed, with decline ranging from 32% (thalamus) to 18% (occipital cortex) over the adult lifespan, or up to 5% per decade. These results in living human subjects corroborate postmortem reports of decline in high affinity nicotine binding with age and may aid in elucidating the role of β 2 -nAChRs in cognitive aging.

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Section: Introductionmentioning

confidence: 82%

Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

Mitsis

Cosgrove

Staley

et al. 2009

Neurobiology of Aging

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“…52 and 53). Cortical ␣4*-nAChR deficits are significantly correlated with cognitive impairment in AD patients (54,55). The major pathological features of AD are A␤ protein deposition and a severe cholinergic deficit.…”

Section: Discussionmentioning

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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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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“…More recently, studies of other pathways linked to AD, including those involving amyloid proteins (Selkoe, 1994), Tau protein (Hellstrom-Lindahl, 2000), and inflammation (Breitner, 1996), have supplanted the cholinergic hypothesis; however, loss of high affinity nicotine binding sites, measured in postmortem tissue or by PET imaging, remains a consistent marker of AD (Nordberg et al, , 1997Kasa et al, 1997;Rusted et al, 2000). A comparable decrease in the binding of other nicotinic agonists has been seen in the brains of patients with AD, including acetylcholine in the presence of atropine, methyl-carbamylcholine, cytisine, epibatidine, and ABT418 (Warpman and Nordberg, 1995;Gotti et al, 1997;Kasa et al, 1997).…”

Section: Cholinergic Hypothesis Of Brain Aging: Studies Of Nachr Exprmentioning

confidence: 99%

“…Further, PD patients given either nicotine patch or allowed to smoke showed improvement in cognitive function (Quik and Jeyarasasingam, 2000). Interestingly, cognitive improvement was correlated with recovery of nicotinic binding resulting from treatment with tacrine, an acetylcholinesterase (AChE) inhibitor (Nordberg et al, 1997), or nerve growth factor (NGF) (Rusted et al, 2000).…”

Section: Effects Of Nicotine On Learning and Memory In Aged Or Dementmentioning

confidence: 99%

Nicotinic receptors in aging and dementia

2002

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Activation of neuronal nicotinic acetylcholine receptors (nAChRs) has been shown to maintain cognitive function following aging or the development of dementia. Nicotine and nicotinic agonists have been shown to improve cognitive function in aged or impaired subjects. Smoking has also been shown in some epidemiological studies to be protective against the development of neurodegenerative diseases. This is supported by animal studies that have shown nicotine to be neuroprotective both in vivo and in vitro. Treatment with nicotinic agonists may therefore be useful in both slowing the progression of neurodegenerative illnesses, and improving function in patients with the disease. While increased nicotinic function has been shown to be beneficial, loss of cholinergic markers is often seen in patients with dementia, suggesting that decreased cholinergic function could contribute to both the cognitive deficits, and perhaps the neuronal degeneration, associated with dementia. In this article we will review the literature on each of these areas. We will also present hypotheses that might address the mechanisms underlying the ability of nAChR function to protect against neurodegeneration or improve cognition, two potentially distinct actions of nicotine.

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Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Cited by 97 publications

References 25 publications

Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

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

Nicotinic receptors in aging and dementia

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