Selective loss of cholinergic neurons in the ventral striatum of patients with Alzheimer disease.

Lehericy, Stéphane; Hirsch, Étienne C.; Cervera, Pascale; Hersh, Louis B.; Hauw, Jean‐Jacques; Ruberg, Merle; Agid, Yves

doi:10.1073/pnas.86.21.8580

Cited by 78 publications

(47 citation statements)

References 30 publications

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“…Although the former project over long distances, the latter are interneurons confined to the striatum area. No significant loss of cholinergic neurons has been observed in the putamen (4), and the enzyme activity estimated on tissue homogenates is reported to be less reduced than in the nbM (1,24). However, neuronal loss (4) and decreased ChoAcTase activity (1) in situ hybridization coupled to immunocytochemistry should help clarify whether the number and state of cholinergic neurons in the striatum (caudate nucleus, putamen, and ventral striatum) of controls and patients with AD differ.…”

Section: Discussionmentioning

confidence: 99%

“…The procedure for coupling immunocytochemical labeling with in situ hybridization was as described by Javoy-Agid et al (19). After (4). The sections were then dehydrated and dipped in emulsion as described above.…”

Section: Methodsmentioning

confidence: 99%

“…A marked loss of immunolabeled cholinergic neurons has been described in the nucleus basalis of Meynert (nbM) (see ref. 3), as well as in the ventral striatum and pallidum (4,5). However, there is a lack of information regarding the functional state of the remaining neurons.…”

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confidence: 99%

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Decreased choline acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease: an in situ hybridization study.

Strada

Vyas

Hirsch

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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The subnormal choline acetyltransferase (ChoAcTase) activity in the cerebral cortex of patients with Alzheimer disease (AD) is thought to originate from the loss of cholinergic neurons in the nucleus basalis of Meynert (nbM). To examine possible changes in the functional activity of the remainng cholinergic neurons in the nbM of patients with AD, the level of expression of ChoAcTase mRNA was evaluated. A procedure for double-labeulng cholinergic neurons to detect ChoAcTase mRNA and the corresponding protein in the same cell was developed, taking advantage of an anti-ChoAcTase antibody and the recently isolated cDNA complementary to a sequence of the human ChoAcTase mRNA. In the study of three controls and four patients with AD, the presence of both ChoAcTase mRNA and protein was observed in the same large neurons in both nbM and putamen. Specificity of in situ hybridization was further supported by the absence ofneuronal sining with a sense probe. In AD patients a subnormal level of expression of ChoAcTase mRNA per cholinergIc cell was detected in the nbM but not in the putamen. Our data support the hypothesis that expression of ChoAcTase mRNA might be down-regulated in the surviving cholinergic neurons in the nbM of patients with AD, raising the possibility of functional restoration by stimulating ChoAcTase synthesis.In Alzheimer disease (AD) a consistent decrease in choline acetyltransferase (ChoAcTase) enzyme activity has been described in the neocortex, as well as in other cholinergic brain areas (1). The reduction in ChoAcTase activity in the cerebral cortex has been reported to be related to the severity of dementia (2). This decrease is thought to originate from loss or declining function of cholinergic neurons known to be affected in AD. A marked loss of immunolabeled cholinergic neurons has been described in the nucleus basalis of Meynert (nbM) (see ref. 3), as well as in the ventral striatum and pallidum (4,5). However, there is a lack of information regarding the functional state of the remaining neurons. Experimental evidence from animal studies suggests that an absence of specific signals, such as trophic factors, can play a crucial role in cholinergic function and cell survival. One of the best known examples is the action of nerve growth factor (NGF) on cholinergic neurons in nbM and striatum (6)(7)(8).In human postmortem brain tissue, the in situ hybridization is a method by which the state of a neuron at the mRNA level can be examined. We have analyzed the levels ofChoAcTase mRNA, taking advantage of the recently isolated cDNA fragment specific for human ChoAcTase, which allowed synthesis of a complementary RNA probe. Expression of ChoAcTase mRNA was examined by in situ hybridization, coupled with immunocytochemical detection of ChoAcTase protein, in the surviving cholinergic neurons in the nbM and in the putamen of AD patients compared with controls. The results show that (i) the RNA probe was specific for human ChoAcTase mRNA, labeling only neurons that were also stained by the antib...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Decreased choline acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease: an in situ hybridization study.

Strada

Vyas

Hirsch

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…[y32P]2N3ATP (specific activity, [5][6][7][8][9][10][11][12][13][14] mCi/,tmol) was then prepared and purified as described for ['t-32P]8N3ATP. Protein molecular size standards were from Bio-Rad.…”

Section: Methodsmentioning

confidence: 99%

“…It has been hypothesized that neurotransmitter systems such as cholinergic (12), monoaminergic (13), and glutamatergic (14) pathways may be involved since they are altered in AD. Specifically, impairment of the glutamatergic neurotransmitter system has been proposed because of the observation of loss in AD of specific pyramidal cells that use glutamate as a neurotransmitter and the observed decrease of specific glutamate receptors (15,16).…”

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confidence: 99%

Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients: a potential diagnostic biochemical marker.

Gunnersen

Haley²

1992

Proc. Natl. Acad. Sci. U.S.A.

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Imaging of cholinergic terminals using the radiotracer [18F](+)-4-fluorobenzyltrozamicol: In vitro binding studies and positron emission tomography studies in nonhuman primates

Mach

Voytko

Ehrenkaufer

et al. 1997

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The goal of the present set of studies was to characterize the in vitro binding properties and in vivo tissue kinetics for the vesicular acetylcholine transporter (VAcChT) radiotracer, [18F](+)-4-fluorobenzyltrozamicol ([18F](+)-FBT). In vitro binding studies were conducted in order to determine the affinity of the (+)- and (-)-stereoisomers of FBT for the VAcChT as well as sigma (sigma 1 and sigma 2) receptors. (+)-FBT was found to have a high affinity (Ki = 0.22 nM) for the VAcChT and lower affinities for sigma 1 (21.6 nM) and sigma 2 (35.9 nM) receptors, whereas (-)-FBT had similar affinities for the VAcChT and sigma 1 receptors (approximately 20 nM) and a lower affinity for sigma 2 (110 nM) receptors. PET imaging studies were conducted in rhesus monkeys (n = 3) with [18F](+)-FBT. [18F](+)-FBT was found to have a high accumulation and slow rate of washout from the basal ganglia, which is consistent with the labeling of cholinergic interneurons in this brain region. [18F](+)-FBT also displayed reversible binding kinetics during the 3 h time course of PET and produced radiolabeled metabolites that did not cross the blood-brain barrier. The results from the current in vitro and in vivo studies indicate that [18F](+)-FBT is a promising ligand for studying cholinergic terminal density, with PET, via the VAcChT.

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Selective loss of cholinergic neurons in the ventral striatum of patients with Alzheimer disease.

Cited by 78 publications

References 30 publications

Decreased choline acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease: an in situ hybridization study.

Decreased choline acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease: an in situ hybridization study.

Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients: a potential diagnostic biochemical marker.

Imaging of cholinergic terminals using the radiotracer [18F](+)-4-fluorobenzyltrozamicol: In vitro binding studies and positron emission tomography studies in nonhuman primates

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