Autoradiographic comparison of [3H](−)nicotine, [3H]cytisine and [3H]epibatidine binding in relation to vesicular acetylcholine transport sites in the temporal cortex in Alzheimer's disease
Section snippets
Drugs
(−)-[N-methyl-3H]nicotine (62.7 and 84.0 Ci/mmol), [3H]cytisine (30.1 and 26.0 Ci/mmol), l-[piperidinyl-3,4-3H]AH5183 ([3H]vesamicol, 50.5 and 35.0 Ci/mmol), and [3H]epibatidine (52.0 and 56.0 Ci/mmol) were purchased from New England Nuclear (NEN Boston, MA, USA). (−)Nicotine hydrogen tartrate salt was obtained from Sigma Chemical Co., St Louis, MO, USA l-(−)vesamicol hydrochloride was purchased from Research Biochemicals International (Natick, MA, USA).
Brain tissues and preparation
Autopsied brain tissue specimens from seven
Results
The results of ApoE genotyping showed that five controls were ApoE ϵ3/3 carrier, one was ApoE ϵ2/3 carrier and one was ApoE ϵ3/4 carrier. Among the AD cases, three patients were ApoE ϵ3/3 carrier, four patients were ϵ3/4 carrier, one was ϵ2/4 carrier and one ϵ4/4 carrier (Table 1). The analysis of ChAT activity indicated a significant decrease in the medial temporal cortex of the AD group (60%; P<0.01; Table 2a).
The autoradiographical distribution of [3H](−)nicotine, [3H]epibatidine, [3
Discussion
The binding of three nicotinic agonists, i.e. [3H](−)nicotine, [3H]epibatidine, and [3H]cytisine, to nAChRs, and that of [3H]vesamicol to VAChT sites, was evaluated in the medial temporal cortex, obtained at autopsy from nine patients with AD and seven controls, by in vitro autoradiography.
The laminar binding distribution of the nAChR ligands in the medial temporal cortex of the controls was similar to that recently observed for post mortem control cases in the superior temporal sulcus,79 with
Conclusions
The laminar binding distribution of the nAChR ligands [3H](−)nicotine, [3H]epibatidine and [3H]cytisine in medial temporal cortex of controls was in general similar, with maxima in layers I, III and V, in the result using quantitative in vitro autoradiography. The binding of all nAChR ligands decreased at older age, especially that of [3H]epibatidine, which may indicate binding to a nAChR subtype that is particularly affected by aging. [3H]Vesamicol showed one binding maximum in the layers
Acknowledgments
The authors sincerely thank Dr Irina Alafuzoff and Dr Ritva Ravid for, respectively, providing the human brain samples from the Huddinge Brain Bank and from the Netherlands Brain Bank in Amsterdam. Kajsa Blomgren is acknowledged for ApoE genotyping, Dr Alf Johansson and Dr Göran Sperber for the help in analysing the autoradiograms, and Drs Larry Frye and Daniel Laryea for linguistical help. This work was financially supported by the Loo and Hans Osterman's foundation, KI foundations and the
References (97)
- et al.
Nicotinic receptor mediates spontaneous GABA release in the rat dorsal motor nucleus of the vagus
Neuroscience
(1997) - et al.
Vesamicol and some of its derivatives: questionable ligands for selectively labeling acetylcholine transporters in rat brain
Eur. J. Pharmac.
(1997) - et al.
Vesamicol analogues as sigma ligands
Biochem. Pharmac.
(1995) - et al.
Vesicular acetylcholine transporter density and Alzheimer's disease
Neurobiol. Aging
(1997) - et al.
Nucleus basalis neuronal loss. Neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease
Neuroscience
(1986) - et al.
Decreased phospholipase A2 activity in Alzheimer brains
Biol. Psychiat.
(1995) - et al.
Cortical cholinergic fibers in aging and Alzheimer's disease: a morphometric study
Neuroscience
(1989) - et al.
Human neuronal nicotinic receptors
Prog. Neurobiol.
(1997) - et al.
Localization of nicotinic cholinergic receptors in rat brain: autoradiographic studies with [3H]cytisine
Neuroscience
(1994) - et al.
Regional distribution of nicotinic receptor subunit mRNAs in human brain: comparison between Alzheimer and normal brain
Molec. Brain Res.
(1999)
Cholinergic enzymes in neocortex, hippocampus and basal forebrain of non-neurological and senile dementia of Alzheimer-type patients
Brain Res.
Alzheimer's disease is a laminar, regional, and neural system specific disease, not a global brain disease
Neurobiol. Aging
[3H]Vesamicol binding in human brain cholinergic deficiency disorders
Neurosci. Lett.
The vesicular acetylcholine transport system
Trends Neurosci.
Regional distribution of subtypes of nicotinic receptors in human brain and effect of aging studied by (±)[3H]epibatidine
Brain Res.
Human brain cholinergic pathways
Prog. Brain Res.
Overlap between acetycholinesterase-rich and choline acetytransferase-positive (cholinergic) axons in human cerebral cortex
Brain Res.
Change in nicotinic receptor subtypes in temporal cortex of Alzheimer brains
Neurosci. Lett.
The role of nicotinic receptors in the pathophysiology of Alzheimer's disease
Prog. Brain Res.
High-affinity choline uptake carrier in Alzheimer's disease: implications for the cholinergic hypothesis of dementia
Brain Res.
Autoradiographic distribution of [3H]nicotine binding in human cortex: relative abundance in subicular complex
J. chem. Neuroanat.
Alteration in nicotinic binding sites in Parkinson's disease, Lewy body disease and Alzheimer's disease: possible index of early neuropathology
Neuroscience
Choline acetyltransferase activity and [3H]vesamicol binding in the temporal cortex of patients with Alzheimer's disease, and rats with basal forebrain lesions
Neuroscience
Immunohisto- and cytochemical localization of cortical nicotinic cholinoceptors in rat and man
Brain Res.
Nicotinic cholinoceptive neurones of the frontal cortex are reduced in Alzheimer's disease
Neurobiol. Aging
Differential involvement of synaptic vesicle and presynaptic plasma membrane proteins in Alzheimer's disease
Biochem. biophys. Res. Commun.
Laminar distribution of nicotinic receptor subtypes in human cerebral cortex as determined by [3H](−)nicotine, [3H]cytisine and [3H]epibatidine in vitro autoradiography
Neuroscience
Immunohistochemical localization of nicotinic beta2 and alpha4 receptor subunits in normal human brain and individuals with Lewy body and Alzheimer's disease: preliminary observations
Neurosci. Lett.
Nicotinic receptors, muscarinic receptors and choline acetyltransferase activity in the temporal cortex of Alzheimer patients with differing apolipoprotein E genotypes
Neurosci. Lett.
Expression of the alpha3 nicotinic receptor subunit mRNA in aging and Alzheimer's disease
Molec. Brain Res.
Lesion with the neurotoxin AF64A alters hippocampal cholinergic receptor function
Brain Res. Bull.
Age-related changes in nicotinic acetylcholine receptor subunits alpha4 and beta2 messenger RNA expression in postmortem human frontal cortex and hippocampus
Neurosci. Lett.
α-Adrenoceptor blocking properties of vesamicol
Eur. J. Pharmac.
Choline acetyltransferase activity and vesamicol binding in Rett syndrome and in rats with nucleus basalis lesions
Neuroscience
Presynaptic nicotinic ACh receptors
Trends Neurosci.
Basal forebrain cholinergic neurons in aged rat brain are more susceptible to ibotenate-induced degeneration than neurons in young adult brain
Brain Res.
Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariant data analysis
Acta neuropath.
[3H]vesamicol binding in brain: autoradiographic distribution, pharmacology, and effects of cholinergic lesions
Synapse
Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's disease
Acta neuropath.
Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele
J. Neurosci.
The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease
Cerebr. Cortex
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Neurology
Multiple cholinergic markers are unexpectedly not altered in the rat dentate gyrus following entorhinal cortex lesions
J. Neurosci.
Comparative ontogenic profile of cholinergic markers, including nicotinic and muscarinic receptors, in the rat brain
J. comp. Neurol.
The autonomic-related cortex: pathology in Alzheimer's disease
Cerebr. Cortex
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
Science
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