Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue3.2001:

Nicotinic Receptor Abnormalities in Alzheimer’s
Disease
Jennifer Court, Carmen Martin-Ruiz, Margaret Piggott, Dean Spurden,
Martin Griffiths, and Elaine Perry
Loss of cortical nicotinic acetylcholine receptors with high
affinity for agonists (20 –50%) in patients with Alzheimer’s disease is a common finding. Recent immunochemical analyses indicate that this deficit is predominantly
associated with the loss of a4 subunits (30 –50%), although modest reductions of a3 may occur in some
individuals (25–29%). No reduction of b2 subunit protein
expression or levels of a3 and a4 messenger RNA has
been reported. Decline in cortical [125I]a-bungarotoxin
binding and a7 protein expression does not appear to be
as extensive or widespread as the loss of a4 (0 – 40%),
with no reduction in messenger RNA expression. In the
thalamus, there was a trend for reduced [3H]nicotine
binding in the majority of nuclei (0 –20%) in Alzheimer’s
disease; however, there was a significant decline in
[125I]a-bungarotoxin binding in the reticular nucleus. In
the striatum [3H]nicotine binding was reduced in Alzheimer’s disease, and although neuroleptic medication accentuated this change, it occurred in those free of neuroleptics. Changes in nicotinic acetylcholine receptors in
Alzheimer’s disease are distinct from those in normal
aging and are likely to contribute to clinical features and
possibly neuropathology. Biol Psychiatry 2001;49:

175–184 © 2001 Society of Biological Psychiatry
Key Words: Nicotinic acetylcholine receptors, Alzheimer’s disease, protein expression, cerebral cortex, thalamus, striatum

Introduction

I

dentification of the loss of cholinergic neurons in the
basal forebrain and of cholinergic innervation of the
cerebral cortex in Alzheimer’s disease (AD) (for reviews,
see Bowen 1983; Cummings and Benson 1987; Perry et al
1994) was followed by investigations into the involvement

From the Joint MRC Newcastle University Centre Development in Clinical Brain
Aging, Institute for the Health of the Elderly, Newcastle General Hospital,
Newcastle upon Tyne, United Kingdom.
Address reprint requests to Jennifer Court, Newcastle General Hospital, Joint MRC
Newcastle University Centre Development in Clinical Brain Aging, Institute
for the Health of the Elderly, MRC Building, Newcastle upon Tyne NE4 6BE,
United Kingdom.

Received May 22, 2000; revised November 27, 2000; accepted December 4, 2000.

© 2001 Society of Biological Psychiatry

of cholinergic receptors. In contrast to choline acetyltransferase, no major or consistent changes in muscarinic
acetylcholine receptors (mAChRs) were observed in the
cerebral cortex (for a review, see Nordberg 1992), although moderate reductions in the cortical M2 receptor
subtype have been reported (Flynn et al 1995). In contrast,
reductions in nicotinic acetylcholine receptors (nAChRs)
(measured using radiolabeled nicotinic agonists such as
[3H]acetylcholine, [3H]nicotine, and [3H]methyl carbamyl
choline at nmol/L concentrations) ranging between 20%
and 50% were consistently observed at autopsy in a
number of neocortical areas and hippocampi of patients
with AD (for reviews, see Court and Perry 1995; Kellar
and Wonnacott 1990; Nordberg 1992). A significant
reduction in [125I]a-bungarotoxin binding to a separate
subtype of nAChRs was also reported in the temporal but
not the frontal cortex in AD (Davies and Feisullin 1981;
Sugaya et al 1990). The functional significance of this

attenuation of brain nAChRs in AD was intriguing, partly
as the density of nAChRs in the normal adult human
neocortex was low relative to mAChRs (around a 40-fold
difference in density; e.g., Court et al 1997) and also since
the precise role(s) of nAChRs in endogenous cholinergic
neurotransmission are unclear (Clarke 1993, 1995).
Extensive research over the last decade has established
that brain nAChRs are a structurally and functionally
diverse group of ligand-gated cation channels that are
associated with numerous transmitter systems for which
they have a modulatory function (Lindstrom et al 1995;
McGehee et al 1995; McGehee and Role 1995; Wonnacott
1997). The majority of receptors with a high affinity for
agonists (nicotine, methyl carbamyl choline, cytisine, and
epibatidine) are composed of a4 and b2 subunits, but
other subunits (e.g., a3 and a6) may play a role in specific
brain pathways (Clarke and Reuben 1996; Le Novere et al
1996) and modify receptor pharmacology (McGehee and
Role 1995). a-Bungarotoxin (aBGT) binds to homomeric
a7-containing receptors, which are characterized by a low

sensitivity to agonists (Clarke 1992), a relatively high
Ca21 conductance (McGehee and Role 1995), and a
central nervous system distribution distinct from nAChRs
with high affinity for agonists in the human brain (Figure
0006-3223/01/$20.00
PII S0006-3223(00)01116-1

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J. Court et al

Figure 1. [3H]Nicotine (A, C) and [125I]abungarotoxin binding (B, D) in the human
hippocampal formation (A, B) and thalamus (C, D) at the level of the lateral
geniculate nucleus. Autoradiography was
according to Court et al (1997) and Spurden
et al (1997) using 1.2 nmol/L [125I]a-bungarotoxin and 4 nmol/L [3H]nicotine. SL,
stratum lacunosum moleculare; S, subiculum; P, presubiculum; LG, lateral geniculate nucleus; E, entorhinal cortex (layers

marked 1– 4); CN, caudate nucleus; PN,
pulvinar nucleus; RN, reticular nucleus.

1) (Court and Perry 1995). Since nAChR subtypes may
represent therapeutic targets with some level of pathway
specificity, and changes in their expression could reflect
disease specific pathology, there is currently great interest
in evaluating nAChR subtype and subunit changes in AD.

Nicotinic Subtype and Subunit Changes in
Cortical Areas
Receptors with High Affinity for Agonists
Early reports that nAChRs with high affinity for agonists
were reduced in neocortical areas relative to age-matched
control subjects have been confirmed by more recent
studies. These include positron emission tomography
(PET) analyses employing (S)(2)[11C]nicotine (Nordberg
et al 1990, 1995), which demonstrated nicotine-binding
deficits in the temporal and frontal cortex in AD in vivo,
although this technique does not control for nonspecific or

endogenous binding and a component of the [11C]nicotine
signal may reflect cerebral blood flow. This attenuation in
nicotinic agonist binding could reflect deficits in both
cortical innervation and intrinsic neurons: messenger
RNAs (mRNAs) for both a3 and a4 subunits have been
reported to be present in cortical neurons (Wevers et al
1994), and experimental lesions in rats indicate the presence of nAChRs with high affinity for agonists associated
with thalamocortical pathways (Prusky et al 1987; Sahin et
al 1992), although their presence on cortical cholinergic
inputs is less certain (Miyai et al 1990; Tilson et al 1989;
Wenk and Rokaeus 1988).

Autoradiographic analysis of [3H]nicotinic binding in
the human hippocampus and adjacent cortex indicates the
highest densities in the subicular complex, stratum lacunosum moleculare, dentate gyrus, and entorhinal cortex
(Perry et al 1992; Court et al, previously unpublished data
[Figure 1]). This pattern of binding suggests an association
with the perforant pathway, although results of a lesion
study in rats would tend to refute this (Aubert et al 1994).
In addition, functional studies of rat tissue indicate

nAChRs with high affinity for agonists may have a
number of functional roles within the hippocampus—for
example, modulation of noradrenaline, acetylcholine, and
g-aminobutyric acid (GABA) release (Alkondon et al
1999; Clarke and Reuben 1996; Wilkie et al 1996).
Reductions in [3H]nicotinic binding in AD of around 30%
relative to age-matched elderly control subjects extend
throughout the hippocampal formation (Perry et al 1995)
(Table 1). This generalized loss in AD would argue against
the reduction in nAChRs being linked with a single
pathway within the hippocampus.
The radioligands [3H]cytisine, [3H]ABT 418, and
3
[ H]epibatidine have allowed a level of selective evaluation of the nAChR loss in AD. Cytisine and ABT 418 are
considered to bind predominantly to a4/b2 subunits,
whereas epibatidine may bind in addition to a3 and
possibly other subunit-containing receptors (Flores et al
1992, 1997; Warpman and Nordberg 1995; Zoli et al
1998). By comparison of [3H]ABT 418 and [3H]epibatidine binding it has been adduced that it is primarily the
former subtype that is lost from the cerebral cortex in AD

Nicotinic Receptors in Alzheimer’s Disease

BIOL PSYCHIATRY
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Table 1. [3H]Nicotine Binding in the Hippocampus
Subfields
CA1
CA2/3
CA4
Stratum lacunosum
Dentate gyrus
Subiculum
Entorhinal cortex 1
Entorhinal cortex 2
Entorhinal cortex 3
Entorhinal cortex 4
Perirhinal cortex

Control

Alzheimer

9.38 6 4.08
7.27 6 3.94
6.32 6 3.03
11.81 6 3.99
10.04 6 4.41
13.16 6 5.26
10.08 6 4.92
11.05 6 4.95
14.45 6 7.25
9.52 6 4.95
12.43 6 6.32

5.98 6 1.62a
6.25 6 2.18
5.45 6 2.58
8.68 6 3.29a

7.53 6 2.11
10.17 6 3.53
7.16 6 2.40
7.77 6 2.49a
10.43 6 3.49
6.92 6 3.33
9.27 6 3.55

Analysis was of 14 control subjects and 14 Alzheimer’s disease (AD) cases,
mean ages 77 6 9 and 80 6 5 years and postmortem delays 29 6 14 and 30 6 17
hours, respectively. Values are means 6 SDs determined using 4 nmol/L [3H]nicotine according to Court et al (1997). For layers 1– 4 in the entorhinal cortex, see
Figure 1A.
a
Indicates significant difference (p , .05, two-sample independent t test).
Overall there was a highly significant trend for reduced [3H]nicotine binding in AD
cases relative to control subjects [two-way analysis of variance, F(1,270) 5 6.47,
p 5 .000].

(Warpman and Nordberg 1995). Nicotinic acetylcholine
receptor subunit deficits are now being actively explored

immunochemically. A consistent pattern emerges from a
number of published reports (Burghaus et al 2000; Guan et
al 2000; Martin-Ruiz et al 1999; Wevers et al 1999) in
relation to a4 subunit protein expression of a reduction in
AD in both neocortical areas and the hippocampus (Table
2). This reduction in the a4 subunit was shown in one
study to be proportional to the loss in epibatidine binding
measured in immediately adjacent sections of cortex in the
same cases (Martin-Ruiz et al 1999). In contrast, a recent
study has indicated no reduction in b2 subunits (Guan et al
2000). A small but statistically significant reduction in the

177

a3 subunit was demonstrated in both the temporal cortex
and the hippocampus by Guan et al (2000), but not by
Martin-Ruiz et al (1999) in the temporal cortex. These data
indicate that the major contributor to the loss of highaffinity nAChRs in cortical areas in AD is likely to be the
a4 subunit, although this does not preclude a minor
contribution from the loss of other subunits. The reduction
in a4 subunit protein does not appear to be the result of
attenuated gene transcription because mRNA levels in AD
appear comparable to those of age-matched control subjects (Hellstrom-Lindahl et al 1999).

a7-Containing Receptors
With regard to a7 nAChR subunit protein expression, the
extent of deficits in cerebral cortical areas in AD may be
more restricted than for a4-containing receptors in terms
of magnitude, areas involved, and consistency between
different groups of cases. No significant difference in
[125I]aBGT binding in the frontal cortex was observed in
two independent studies (Davies and Feisullin 1981;
Sugaya et al 1990), and although the early study of Davies
and Feisullin reported a 40% reduction in the temporal
cortex, this was not replicated by a more recent analysis
(Hellstrom-Lindahl et al 1999). This lack of a consistent
deficit in cortical aBGT binding in AD cases is perhaps
surprising because lesions of the basal forebrain in rats
suggest that these receptors are at least partly present on
cholinergic terminals (Sugaya et al 1991).
In the hippocampus a 25% reduction in [125I]aBGT
binding (using membrane homogenates) was observed in
AD relative to age-matched control subjects, although the
number of control cases studied was small (n 5 4)

Table 2. Percentage Changes in Cortical a4, a3, and b2 nAChR Subunit Expression in Alzheimer’s Disease (CAD) Relative to
Age-Matched Control Subjects
Study
Protein expression—Western blot
Martin-Ruiz et al 1999
Guan et al 2000
Burghaus et al 2000
Immunohistochemistryb
Wevers et al 1999
mRNA expression
Terzano et al 1998
(in situ hybridization)
Hellstrom-Lindahl et al 1999
(RT-PCR)

Number of cases

a4

a3

15 control subjects
14 AD
8 control subjects
8 AD
5 control subjects
5 AD

49 (35a)2

NSD

472
352
402

292
252

5 control subjects
6 AD
7 control subjects
7 AD
5-6

b2

Temporal cortex
NSD
NSD

30 –592

NSD
NSD

Brain region

Temporal cortex
Hippocampus
Temporal cortex

Frontal cortex

NSD
NSD
NSD
NSD

NSD, no statistically significant difference; mRNA, messenger RNA; RT-PCR, quantitative reverse transcription polymerase chain reaction.
a
Decrease relative to known nonsmoking control subjects.
b
The measure applied was the ratio of the number of cells expressing a4 immunoreactivity/the number of cells expressing a4 mRNA.

Hippocampus
Entorhinal cortex
Temporal cortex
Hippocampus

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J. Court et al

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Table 3. [125I]a-Bungarotoxin Binding in the Hippocampus
Subfields
CA1
CA2/3
CA4
Dentate gyrus
Subiculum
Perirhinal cortex
Entorhinal cortex

Control

Alzheimer

3.43 6 2.19
2.23 6 1.58
2.60 6 2.06
2.27 6 1.68
2.78 6 1.25
2.78 6 1.89
3.11 6 2.05

2.94 6 1.94
3.52 6 2.78
2.88 6 2.02
3.46 6 2.33
2.62 6 1.66
2.34 6 2.21
3.35 6 2.21

Analysis was of 14 control subjects and 14 Alzheimer’s disease (AD) cases,
mean ages 77 6 9 and 80 6 5 years and postmortem delay, 29 6 14 and 30 6 17
hours, respectively. Values are means 6 SDs determined using 1.2 nmol/L
[125I]a-bungarotoxin according to Court et al (1997). No significant difference was
found between AD and control subjects.

(Hellstrom-Lindahl et al 1999). In a larger autoradiographic analysis of [125I]aBGT binding in the hippocampal formation and entorhinal cortex (n 5 14 in AD and
control groups), considerable variation between cases,
particularly AD ones, was observed, and there were no
consistent or statistically significant differences between
groups in any subarea (previously unpublished data) (Table 3).
Reports of Western blot analyses using antibodies
directed against a7 subunit sequences also suggest no
significant or only minor reductions in the temporal cortex
in AD (Burghaus et al 2000; Guan et al 2000; Martin-Ruiz
et al 1999) (Table 4). In the one study of a7 protein
expression in the hippocampus a 36% reduction in AD
cases relative to control subjects was reported (Guan et al
2000), and an immunochemical study also suggested a
reduction in the number of cells expressing a7 protein in
the frontal cortex in AD (Wevers et al 1999). In terms of
mRNA expression of the a7 subunit, no difference was
observed between AD and control subjects in the temporal

cortex, but interestingly a 65% increase was observed in
the hippocampus (Hellstrom-Lindahl et al 1999). The
latter finding might indicate that a compensation mechanism involving increased transcription of the a7 gene in
the hippocampus occurs in a proportion of patients with
AD. The potential importance of this finding, together
with the relatively small numbers of cases, warrants
further investigation.

Subcortical Areas
Nicotinic Receptors in the Thalamus in AD
The thalamus is a brain area of particularly intense
expression of nAChRs. The density of nicotinic agonist
binding in the human thalamus is high in the majority of
nuclei, most strikingly in the lateral geniculate, medial
geniculate, and anterior (Figure 1 and Table 5) (Breese et
al 1997b; Spurden et al 1997; Xuereb et al 1990). a3 and,
to a lesser extent, b2 subunit mRNAs are expressed in
thalamic nuclei in the human thalamus (Rubboli et al
1994) and high levels of expression of a3, a4, and b2
mRNAs occur in the rodent thalamus (Marks et al 1992;
Wada et al 1989), suggesting that nAChRs with high
affinity for agonists are at least in part present on intrinsic
neurons within this brain structure. In contrast to highaffinity agonist binding, [125I]aBGT binding and a7
mRNA are only highly expressed in the reticular nucleus
of the thalamus, with considerably lower densities in other
nuclei (Figure 1 and Table 6) (Breese et al 1997a; Spurden
et al 1997).
Recent, novel, autoradiographic analysis of [3H]nicotine binding (Table 5) confirms an earlier report of no
major deficits in AD patients relative to age-matched

Table 4. Percentage Changes in a7 Nicotinic Acetylcholine Receptors in Alzheimer’s Disease
(AD) Relative to Age-Matched Control Subjects
Study
Protein expression by Western blot
Martin-Ruiz et al 1999
Guan et al 2000
Burghaus et al 2000
Immunohistochemistrya
Wevers et al 1999
mRNA by quantitative RT-PCR
Hellstrom-Lindahl et al 1999

Number of cases

Change

Brain area

15 control subjects
14 AD
8 control subjects
8 AD
5 control subjects
5 AD

NSD

Temporal cortex

NSD
362
162

Temporal cortex
Hippocampus
Temporal gyrus

5 control subjects
6 AD

20 – 622

Frontal cortex

5– 6

NSD
NSD
651

Temporal cortex
Cerebellum
Hippocampus

NSD, no statistically significant difference; mRNA, messenger RNA; RT-PCR, quantitative reverse transcription polymerase
chain reaction.
a
The measure applied was the ratio of the number of cells expressing a7 immunoreactivity/the number of cells expressing a7
mRNA.

Nicotinic Receptors in Alzheimer’s Disease

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Table 5. [3H]Nicotine Binding in the Thalamus
Nuclei
Anterior
Ventral anterior
Ventral lateral
Mediodorsal
Parafascicular
Centromedian
Ventroposteriormedial
Ventroposteriorlateral
Lateral dorsal
Lateral posterior
Pulvinar
Reticular
Lateral geniculate
Medial geniculate

Control (N)

Alzheimer (N)

28.72 6 7.49 (7)
18.55 6 4.38 (6)
17.83 6 8.33 (6)
23.31 6 4.71 (9)
10.82 6 3.36 (4)
3.62 6 3.45 (3)
17.70 6 2.58 (3)
12.08 6 3.8 (8)
23.36 6 1.53 (4)
20.17 6 6.60 (6)
20.45 6 3.60 (7)
11.94 6 2.90 (11)
31.65 6 5.93 (6)
29.54 6 6.02 (4)

23.87 6 5.38 (13)
14.72 6 4.92 (6)
16.50 6 4.94 (11)
23.80 6 4.80 (11)
8.94 6 4.10 (5)
4.67 6 4.32 (4)
15.89 6 5.39 (4)
10.35 6 4.31 (5)
19.44 6 2.60 (4)
16.46 6 5.13 (5)
17.37 6 5.85 (7)
12.84 6 3.99 (12)
26.17 6 5.86 (6)
25.02 6 4.32 (6)

Results are means 6 SDs. Binding was measured using 4 nmol/L [3H]nicotine
according to Spurden et al (1997). Eleven control and 13 Alzheimer’s disease (AD)
cases were used for the analysis, mean ages 76 6 14 and 80 6 9 years and
postmortem delays 28 6 11 and 31 6 15 hours, respectively. Tissue for all nuclei
was not available for all cases. Although there was no significant difference in
binding for any nucleus between AD and control cases, two-way analysis of
variance indicated a significant overall trend for reduced [3H]nicotine binding in
AD [F(1,155) 5 9.21, p 5 .003]. N, number of determinations.

control subjects (Xuereb et al 1990); however, there was a
trend for [3H]nicotine binding to be lower in the majority
of nuclei in AD (Table 5) [two-way analysis of variance of
density in both groups and all areas indicated a significant
difference between AD and control cases; F(1,55) 5 9.21,
p 5 .003]. For [125I]aBGT binding there was a significant
reduction of 34% in the overall density in the reticular
nucleus in AD (p 5 .021, independent t test) and a greater
reduction (50%, p , .001) in islands of cells within the
reticular nucleus, which showed more intense binding
(Figure 1 and Table 6). This loss of [125I]aBGT binding is
Table 6. [125I]a-Bungarotoxin Binding in the Thalamus
Nuclei
Anterior
Ventral anterior
Ventral lateral
Mediodorsal
Centromedian
Ventroposteriormedial
Ventroposteriorlateral
Lateral posterior
Pulvinar
Reticular (overall)
Reticular (areas of
particularly high intensity)
Lateral geniculate
Medial geniculate

Control (N)

Alzheimer (N)

1.00 6 0.77 (6)
1.44 6 1.18 (4)
1.41 6 0.65 (7)
1.35 6 0.38 (6)
1.66 6 1.32 (4)
1.37 6 0.96 (5)
1.61 6 0.38 (3)
1.35 6 1.09 (5)
1.22 6 0.68 (7)
6.29 6 1.84 (11)
14.10 6 4.03 (10)

1.14 6 0.84 (13)
1.14 6 1.25 (8)
1.91 6 1.13 (7)
1.84 6 1.04 (9)
1.97 6 0.92 (5)
1.90 6 0.35 (5)
1.64 6 0.71 (8)
1.67 6 0.71 (8)
1.42 6 1.17 (4)
4.16 6 2.31 (13)a
7.20 6 3.58 (13)a

2.17 6 1.24 (5)
1.03 6 1.02 (4)

2.29 6 1.51 (7)
2.00 6 1.28 (4)

Results are means 6 SDs. Binding was measured using 1.2 nmol/L [125I]abungarotoxin according to Spurden et al (1997). Eleven control and 13 Alzheimer’s
disease (AD) cases were used for the analysis, mean ages 76 6 14 and 80 6 9 years
and postmortem delays 28 6 11 and 31 6 15 hours, respectively. Tissue for all
nuclei were not available for all cases. N, number of determinations.
a
Significant difference between AD and control values (p , .05, two-sample
independent t test).

179

not apparently specific for AD, since a similar reduction
was observed in dementia with Lewy bodies and schizophrenia (Court et al 1999), which raises issues of its
etiopathologic and clinical significance. The reticular nucleus receives input from the basal forebrain (Chen and
Bentivoglio 1993), so that reduced [125I]aBGT binding
may reflect presynaptic sites on attenuated cholinergic
afferents. Interestingly, this nucleus is also particularly
susceptible to cortical hypoxia (Hossmann 1999), possibly
via uncontrolled glutamate release from numerous cortical
inputs. Reduced [125I]aBGT binding in AD could therefore also reflect a loss of postsynaptic receptors on
neurons within the reticular nucleus as a consequence of
attrition of cortical glutamatergic neurons and disruption
of energy metabolism in AD (Minoshima et al 1999;
Rapoport 1999). Reduced facilitation of GABAergic neurons within this nucleus, which is involved in synchronizing thalamic activity, may contribute to the noncognitive
deficits (e.g., those in sensory processing giving rise to
hallucinations) observed in AD. There was no significant
change in [125I]aBGT binding in any other thalamic nuclei
(Table 6).

Nicotinic Receptors in the Striatum in AD
Some previous autopsy studies, but not all, indicate
reductions in high-affinity nicotinic agonist binding in the
striatum (particularly in the caudate nucleus) in AD
(Aubert et al 1992; Perry et al 1989; Rinne et al 1991;
Shimohama et al 1986). These deficits, present in at least
some AD patients, are likely to be associated with disorders of movement and mood observed in late stages of
AD. However, a proportion of patients will have received
long-term medication for the treatment of noncognitive
symptoms, most notably with traditional neuroleptics.
These drugs have a major effect on nigrostriatal dopaminergic neurons, on which a high proportion of nAChRs are
believed to be sited within the striatum (Clarke and Pert
1985). In a recent study from our laboratory (Court et al
2000) patients with AD taking neuroleptics tended to have
greater loss of striatal [3H]nicotine binding than those who
had not, although this was not as marked as in patients
with Lewy body dementia (who suffer moderate loss of
substantia nigra dopaminergic neurons) (Figure 2), and
there was still a significant reduction of striatal [3H]nicotine binding in AD patients free of neuroleptics relative to
age-matched control subjects.
In Parkinson’s disease the loss of striatal [3H]nicotine
binding by 40 –70% closely parallels the loss of nigrostriatal dopaminergic markers; however, this is not the case in
AD (Table 7), suggesting a different mechanism occurring
in AD leading to striatal nAChR loss. In AD, loss of
nAChRs possibly situated on striatal intrinsic GABAergic

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Figure 2. [3H]Nicotine binding and dopamine levels in the
caudate nucleus in Alzheimer’s disease (AD) and dementia with
Lewy bodies (DLB), derived from Court et al (in press).
Subgroups of patients taking neuroleptic medications and those
free of neuroleptics are indicated by 1nl and 2nl, respectively.
Bars are means 6 SDs, and the figures on bars the number of
cases. All means are significantly different from control subjects
(p , .05). *Subgroups of DLB patients (2nl vs. 1nl) were
significantly different (p , .05).

or cholinergic neurons or glutamatergic or serotonergic
afferents may occur.

groups, also in the striatum after the age of 70 years but
not in the thalamus (Hellstrom-Lindahl and Court, in
press; Nordberg 1993). However, more detailed analysis
of nAChR expression indicates that patterns of change
with age are not consistently reflected in AD. In the
different subfields of the hippocampal formation the rate
of change during senescence varies—for example, being
more striking in the entorhinal cortex than the CA1 (Court
et al 1997)— but in AD these areas display a similar
magnitude of decline (Table 1). There is also evidence to
suggest that the significant reductions in a3 and b2
subunit mRNA expression in the human cerebral cortex
with age (Terzano et al 1998; Tohgi et al 1998) are not
reflected in AD (Table 2). In addition, the reduction in
[125I]aBGT binding in the entorhinal cortex observed with
normal aging (Court et al 1997) was not paralleled by
reduced [125I]aBGT binding in this area in AD (Table 3).
These results indicate that the mechanisms involved in
age-related nAChR loss may not be similar to those
occurring in AD, but rather that changes taking place
during normal aging may be one of the factors that
predispose patients to the specific deficits that develop in
AD.

Relationship to Normal Aging

Relationship of nAChR Loss to Alzheimer’s
Pathology

In some respects, reductions in nAChRs in AD, particularly of those with high affinity for agonists, may be
viewed as an accentuation of the normal process of aging.
Reductions in these receptors in cortical areas with advancing age in humans have been reported by many

A key question is whether changes in nAChRs in AD are
simply a reflection of neuronal pathology or are a significant contributing factor to the etiology of AD. There is no
doubt that attenuation of nAChR binding occurs in areas
of notable pathology in AD, and a number of studies

Table 7. Basal Ganglia Changes in Alzheimer’s (AD) and Parkinson’s (PD) Diseases

SN pars compacta neuronsa
Dopaminea
Caudate
Putamen
HVA/DAc
Caudate
Putamen
[3H]nicotine binding (fmol/mg tissue
equivalent)d
Ventral caudate
Dorsal putamen
ChATaef
Striatum

Control

Alzheimer

Parkinson

494 6 142

489 6 197

156 6 82b

9.01 6 3.21
8.44 6 3.06

N
N

s50%
s80%

N
N

a300%
a1,000%

5.06 6 1.64b
6.26 6 1.26b

5.10 6 2.95b
2.74 6 1.88b

sN

N

Nicotine binding: control subjects N 5 42, AD N 5 13, PD N 5 13. Arrows indicate differences relative to control subjects.
SN, substantia nigra; HVA/DA, homovanillic acid/dopamine; ChAT, choline acetyltransferase.
a
Data derived from Perry et al (1998).
b
Significant difference from control subjects (p , .05).
c
Data derived from Piggott et al (1998).
d
Data derived from Court et al (2000).
e
Data derived from Aubert et al (1992).
f
Data derived from Shimohama et al (1986).

Nicotinic Receptors in Alzheimer’s Disease

indicate a significant correlation between AD pathology
and nAChR loss. Even in the striatum, where diseaserelated changes in dopamine parameters do not occur as in
Parkinson’s disease (Table 7), pathology in terms of
amyloid accumulation and loss of choline acetyltransferase has been reported (Gearing et al 1997; Perry et al
1998; Shimohama et al 1986). There appears to be a
relationship between nicotinic receptor density and cognitive function: in both in vivo and autopsy studies the
intensity of high-affinity nicotinic agonist binding in the
temporal cortex has been significantly correlated to dementia rating (Nordberg et al 1995; Perry et al 2000).
Further, treatment of AD patients with an acetylcholinesterase inhibitor was associated with both an improvement
of cognitive performance and an increase in nicotine
binding as measured by PET (Nordberg 1999). In relation
to the loss of cortical synapses in AD, [3H]epibatidine has
been shown to be positively correlated with synaptophysin
immunoreactivity (Sabbagh et al 1998). [3H]Epibatidine
binding at autopsy in the temporal cortex has also been
demonstrated to be inversely correlated with b-amyloid
(Ab) 1– 42 content in the temporal cortex, although not
with amyloid plaque or neurofibrillary tangle density in a
group of 81 patients with a range of Clinical Dementia
Rating from 0 to 5 (Perry et al 2000). This suggests that it
is the accumulation of what is generally believed to be the
toxic amyloid component contributing to senile plaque
formation that is associated with the loss of nicotine
binding. In contrast, a positive correlation between
[125I]aBGT binding and plaque density was observed in
both AD cases and elderly control subjects in the entorhinal cortex (Perry et al 2000). The significance of this
finding is at present uncertain, in particular in light of the
findings suggesting that Ab 1– 42 binds with high affinity
to aBGT binding sites (Wang et al 2000).
A possible functional link between nAChRs and ADtype pathology is also indicated by two studies comparing
cortical amyloid plaque and neurofibrillary tangle densities in tobacco smokers and nonsmokers. In both normal
elderly individuals (Perry et al 2000) and groups of
unselected cases coming to autopsy (Ulrich et al 1997),
plaques but not tangles were significantly fewer in tobacco-smoking groups. A number of case-control and follow-up studies have also indicated that tobacco use may be
associated with a reduced risk of developing AD and a
delayed onset of familial AD (for a review, see Lee 1994).
However, a more recent population-based study (Rotterdam) demonstrated a significantly increased risk of developing AD in smokers (Ott et al 1998). There is likely to be
a complex relationship between tobacco use and the
incidence of dementia, which may be complicated by
established adverse effects of smoking on cardio- and
cerebrovascular systems and interactions between amyloid

BIOL PSYCHIATRY
2001;49:175–184

181

and microvascular pathology in AD (Kalaria 1997). Investigations of the effects of long-term exposure to nicotinic
drugs in appropriate animal models are required to confirm that the differences reported above were not the result
of confounding variables. However, the possibility that
nAChRs have a role in protecting aging neurons is
strongly suggested by the demonstration that transgenic
b2 knockout mice develop accelerated age-related brain
pathology, in terms of hippocampal neuron loss and
enhanced gliosis (Zoli et al 1999).

Conclusions
Although deficits in nAChRs in AD have long been
recognized, the extent, subunit specificity, and consequences of these phenomena are only now being evaluated. The most consistently observed change in nAChR
expression in AD is the loss in cerebral cortical areas of
the a4 subunit and a4-containing receptors. In addition to
the need to examine further subunit deficits in more brain
areas in AD to elucidate the potential for targeting nicotinic therapy, investigation of these deficits should be
related to prospectively assessed behavioral and cognitive
symptoms in patients. It is likely that some of the
variability observed between different studies of relatively
small groups of patients—for example, those for a3 and
a7 expression—is a reflection of unrecognized differences
between subgroups of patients, possibly in terms of
different genetic subgroups and noncognitive symptoms.

This work was supported by the Medical Research Council, London.
CM-R was a European Community TMR research fellow.
Aspects of this work were presented at the symposium “Nicotine
Mechanisms in Alzheimer’s Disease,” March 16 –18, 2000, Fajardo,
Puerto Rico. The conference was sponsored by the Society of Biological
Psychiatry through an unrestricted educational grant provided by Janssen
Pharmaceutica L.P.

References
Alkondon M, Pereira EF, Einsenberg HM, Albuquerque EX
(1999): Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate
GABA release from CA1 interneurons in rat hippocampal
slices. J Neurosci 19:2693–2705.
Aubert I, Araujo DM, Cecyre D, Robitaille Y, Gauthier S,
Quirion R (1992): Comparative alterations of nicotinic and
muscarinic binding sites in Alzheimer’s and Parkinson’s
diseases. J Neurochem 58:529 –541.
Aubert I, Poirier J, Gauthier S, Quirion R (1994): Multiple
cholinergic markers are unexpectedly not altered in the rat
dentate gyrus following entorhinal cortex lesions. J Neurosci
14:2476 –2484.
Bowen DM (1983): Biochemical assessment of neurotransmitter
and metabolic dysfunction and cerebral atrophy in Alzhei-

182

BIOL PSYCHIATRY
2001;49:175–184

mer’s disease. In: Katzman R, editor. Biological Aspects of
Alzheimer’s Disease. Cold Spring Harbor, NY: Cold Spring
Harbor Laboratory, 219 –232.
Breese CR, Adams C, Logel J, Drebing C, Rollins Y, Barnhart Y,
et al (1997a): Comparison of regional expression of nicotinic
acetylcholine receptor alpha 7 mRNA and [125I]-alphabungarotoxin binding in postmortem brain. J Comp Neurol
387:385–398.
Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins
AC, et al (1997b): Effect of smoking history on [3H]nicotine
binding in human postmortem brain. J Pharmacol Exp Ther
282:7–13.
Burghaus L, Schutz U, Krempel U, de Vos RA, Jansen Steus EN,
Wevers A, et al (2000): Quantitative assessment of nicotinic
acetylcholine receptor proteins in the cerebral cortex of
Alzheimer’s patients. Brain Res Mol Brain Rev 76:385–388.
Chen S, Bentivoglio M (1993): Nerve growth factor receptorcontaining cholinergic neurons of the basal forebrain project
to the thalamic reticular nucleus of the rat. Brain Res
606:207–221.
Clarke P (1995): Nicotinic receptors and cholinergic neurotransmission in the central nervous system. Ann N Y Acad Sci
757:73– 83.
Clarke PB (1992): The fall and rise of neuronal alpha-bungarotoxin binding proteins. Trends Pharmacol Sci 13:407– 413.
Clarke PB (1993): Nicotinic receptors in mammalian brain:
Localization and relation to cholinergic innervation. Prog
Brain Res 98:77– 83.
Clarke PB, Reuben M (1996): Release of [3H]-noradrenaline
from rat hippocampal synaptosomes by nicotine: Mediation
by different nicotinic receptor subtypes from striatal [3H]dopamine release. Br J Pharmacol 117:595– 606.
Clarke PBS, Pert A (1985): Autoradiographic evidence for
nicotine receptors on nigralstriatal and mesolimbic dopaminergic neurons. Brain Res 348:355–358.
Court J, Piggott M, Lloyd S, Cookson N, Ballard C, McKeith I,
et al (2000): Nicotine binding in human striatum: Elevation in
schizophrenia and reductions in dementia with Lewy bodies,
Parkinson’s disease and Alzheimer’s disease and in relation
to neuroleptic medication. Neuroscience 98:79 – 87.
Court J, Spurden D, Lloyd S, McKeith I, Ballard C, Cairns N, et
al (1999): Neuronal nicotinic receptors in dementia with
Lewy bodies and schizophrenia: a-Bungarotoxin and nicotine
binding in the thalamus. J Neurochem 73:1590 –1597.
Court JA, Lloyd S, Johnson M, Griffiths M, Birdsall NJM,
Piggott MA, et al (1997): Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation
during development and aging. Dev Brain Res 101:93–105.
Court JA, Perry EK (1995): Distribution of nicotinic receptors in
the CNS. In: Stone TW, editor. CNS Neurotransmitters and
Neuromodulators. London: CRC Press, 85–104.
Cummings JL, Benson DF (1987): The role of the nucleus basalis
of Meynert and dementia: Review and reconsideration. Alzheimer Dis Assoc Disord 1:128 –145.
Davies P, Feisullin S (1981): Postmortem stability of a-bungarotoxin binding sites in mouse and human brain. Brain Res
216:449 – 454.
Flores CM, Da´vila-Garcı´a M, Ulrich YM, Kellar KJ (1997):
Differential regulation of neuronal receptor binding sites

J. Court et al

following chronic nicotine administration. J Neurochem 69:
2216 –2219.
Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ
(1992): A subtype of nicotinic cholinergic receptor in rat
brain is composed of alpha 4 and beta 2 subunits and is
up-regulated by chronic nicotine treatment. Mol Pharmacol
41:31–37.
Flynn DD, Ferrari-DiLeo G, Levey AI, Mash DC (1995):
Differential alterations in muscarinic receptor subtypes in
Alzheimer’s disease: Implications for cholinergic based therapies. Life Sci 56:869 – 876.
Gearing M, Levey AI, Mirra SS (1997): Diffuse plaques in the
striatum in Alzheimer’s disease (AD): Relationship to the
striatal mosaic and selected neuropeptide markers. J Neuropathol Exp Neurol 56:1363–1370.
Guan Z-Z, Zhang X, Ravid R, Nordberg A (2000): Decreased
protein levels of nicotinic receptor subunits in the hippocampus and temporal cortex of patients with Alzheimer’s disease.
J Neurochem 74:237–243.
Hellstrom-Lindahl E, Court JA (in press): Nicotinic acetylcholine receptors during pre-natal development and brain pathology in human aging. Behav Brain Res.
Hellstrom-Lindahl E, Mousavi M, Zhang X, Ravid R, Nordberg
A (1999): Regional distribution of nicotinic receptor subunit
mRNAs in human brain: Comparison between Alzheimer and
normal brain. Mol Brain Res 66:94 –103.
Hossmann K (1999): The hypoxic brain. Insights from ischemic
research. Adv Exp Biol Med 474:155–169.
Kalaria RN (1997): Cerebrovascular degeneration is related to
amyloid-beta protein deposition in Alzheimer’s disease. Ann
N Y Acad Sci 826:263–271.
Kellar KJ, Wonnacott S (1990): Nicotinic cholinergic receptors
in Alzheimer’s disease. In: Wonnacott S, Russell MAH,
Stolerman IP, editors. Nicotine Psychopharmacology: Molecular, Cellular and Behavioural Aspects. Oxford, UK: Oxord
University Press, 341–373.
Lee PN (1994): Smoking and Alzheimer’s disease: A review of
the epidemiological evidence. Neuroepidemiology 13:131–
144.
Le Novere N, Zoli M, Changeux J-P (1996): Neuronal nicotinic
receptor alpha 6 subunit mRNA is selectively concentrated in
catecholaminergic nuclei of the rat brain. Eur J Neurosci
8:2428 –2439.
Lindstrom J, Anand R, Peng X, Gerzanich V, Wang F, Li Y
(1995): Neuronal nicotinic receptor subtypes. Ann N Y Acad
Sci 757:100 –116.
Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, Heinemann SF, Collins AC (1992): Nicotine binding
and nicotinic receptor subunit RNA after chronic nicotine
treatment. J Neurosci 12:2765–2784.
Martin-Ruiz CM, Court JA, Molnar E, Lee M, Gotti C, Mamalaki A, et al (1999): a4 but not a3 and a7 nicotinic
acetylcholine receptor subunits are lost from the temporal
cortex in Alzheimer’s disease. J Neurochem 73:1635–1640.
McGehee DS, Heath MJS, Gelber S, Devay P, Role LW (1995):
Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269:1692–
1696.
McGehee DS, Role LW (1995): Physiological diversity of

Nicotinic Receptors in Alzheimer’s Disease

nicotinic acetylcholine receptors expressed by vertebrate
neurons. Ann Rev Physiol 57:521–546.
Minoshima S, Cross D, Foster N, Henry T, Kuhl D (1999):
Discordance between tradtional pathology and energy metabolic changes in very early Alzheimer’s disease. Pathophysiological implications. Ann N Y Acad Sci 893:350 –352.
Miyai I, Ueno S, Yorifuji S, Fujimura H, Tarui S (1990):
Alterations in neocortical expression of nicotinic acetylcholine receptor mRNAs following unilateral lesions of the rat
nucleus basalis magnocellularis. J Neural Transm 82:79 –91.
Nordberg A (1992): Neuroreceptor changes in Alzheimer disease. Cerebrovasc Brain Metab Rev 4:303–328.
Nordberg A (1993): Neuronal nicotinic receptors and their
implications in ageing and neurodegenerative disorders in
mammals. J Reprod Fertil Suppl 46:145–154.
Nordberg A (1999): PET studies and cholinergic therapy in
Alzheimer’s disease. Rev Neurol (Paris) 155(suppl 4):S53–
S63.
Nordberg A, Hartvig P, Lilja A, Viitanen M, Winblad B (1990):
Decreased uptake and binding of 11C-nicotine in brain of
Alzheimer patients as visualized by positron emission tomography. J Neural Transm Park Dis Dement Sect 2:215–224.
Nordberg A, Lundqvist H, Hartvig P, Lilja A, Langstrom B
(1995): Kinetic analysis of regional (S)(2)11C-nicotine binding in normal and Alzheimer brains—in vivo assessment
using positron emission tomography. Alzheimer Dis Assoc
Disord 9:21–27.
Ott A, Slooter AJC, Hofman A, van Harskamp F, Witteman
JCM, van Broeckhoven C, van Duijin CM, Breteler MMB
(1998): Smoking and risk of dementia and Alzheimer’s
disease in a population-based cohort study: The Rotterdam
study. Lancet 351:1840 –1843.
Perry E, Court J, Goodchild R, Griffiths M, Jaros E, Johnson M,
et al (1998): Clinical neurochemistry: Developments in dementia research based on brain bank material. J Neural
Transm 105:915–933.
Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott
M, et al (2000): Nicotinic receptor subtypes in human brain
ageing, Alzheimer and Lewy body diseases. Eur J Pharmacol
393:215–222.
Perry EK, Court JA, Johnson M, Piggott MA, Perry RH (1992):
Autoradiographic distribution of [3H]nicotine binding in human cortex: Relative abundance in subicular complex.
J Chem Neuroanat 5:399 – 405.
Perry EK, Court JA, Piggott MA, Perry RH (1994): Cholinergic
component of dementia and aging. In: Huppert FA, Brayne C,
O’Connor DW, editors. Dementia and Normal Aging. New
York: Cambridge University Press, 437– 469.
Perry EK, Morris CM, Court JA, Cheng A, Fairbairn AF,
McKeith IG, et al (1995): Alteration in nicotine binding sites
in Parkinson’s disease, Lewy body dementia and Alzheimer’s
disease: Possible index of early neuropathology. Neuroscience 64:385–395.
Perry EK, Smith CJ, Perry RH, Johnson M, Fairbairn AF (1989):
Nicotine (3H-nicotine) receptor binding in human brain:
Characterization and involvement in cholinergic neuropathology. Neurosci Res Commun 5:117–124.
Piggott MA, Perry EK, Marshall EF, McKeith IG, Johnson M,
Melrose HL, et al (1998): Nigrostriatal dopaminergic activi-

BIOL PSYCHIATRY
2001;49:175–184

183

ties in dementia with Lewy bodies in relation to neuroleptic
sensitivity: Comparisons with Parkinson’s disease. Biol Psychiatry 44:765–774.
Prusky GT, Shaw C, Cynader MS (1987): Nicotine receptors are
located on lateral geniculate nucleus terminals in cat visual
cortex. Brain Res 412:131–138.
Rapoport S (1999): In vivo PET imaging and postmortem studies
suggest potentially reversible and irreversible stages of brain
metabolic failure in Alzheimer’s disease. Eur Arch Psychiatry
Clin Neurosci 249:46 –55.
Rinne J, Myllykyla¨ T, Lo¨nnberg P, Marjama¨ki P (1991): A
postmortem study of brain nicotinic receptors in Parkinsonson’s disease and Alzheimer’s disease. Brain Res 547:167–
170.
Rubboli F, Court JA, Sala C, Morris C, Chini B, Perry E,
Clementi F (1994): Distribution of nicotinic receptors in the
human hippocampus and thalamus. Eur J Neurosci 6:1596 –
1604.
Sabbagh M, Reid R, Corey-Bloom J, Rao T, Hansen L, Alford
M, et al (1998): Correlations of nicotinic binding with
neurochemical markers in Alzheimer’s disease. J Neural
Transm 105:709 –717.
Sahin M, Bowen WD, Donoghue JP (1992): Location of nicotinic and muscarinic cholinergic and mu-opiate receptors in
rat cerebral neocortex: Evidence from thalamic and cortical
lesions. Brain Res 579:135–147.
Shimohama S, Tanniguchi T, Fujiwara M, Kameyama M (1986):
Changes in nicotinic and muscarinic cholinergic receptors in
Alzheimer’s-type dementia. J Neurochem 46:288 –293.
Spurden D, Court J, Lloyd S, Oakley A, Perry R, Pearson C, et
al (1997): Nicotinic receptor distribution in the human thalamus: Autoradiographical localization of [3H]nicotine and
[125I]abungarotoxin binding. J Chem Anat 13:105–113.
Sugaya K, Downen M, Giacobini E (1991): Nucleus basalis
lesions decrease a- and k-bungarotoxins binding in rat cortex.
Neuroreport 2:177–180.
Sugaya K, Giacobini E, Chiappinelli VA (1990): Nicotinic
acetylcholine receptor subtypes in human frontal cortex:
Changes in Alzheimer’s disease. J Neurosci Res 27:349 –359.
Terzano S, Court J, Fornasari D, Griffiths M, Spurden D, Lloyd
S, et al (1998): Expression of the a3 nicotinic receptor
subunit mRNA in human brain in aging and Alzheimer’s
disease. Mol Brain Res 63:72–78.
Tilson H, Schwartz R, Ali S, McLamb R (1989): Colchicine
administered into the area of the nucleus basalis decreases
cortical nicotinic cholinergic receptors labelled by [3H]nicotine. Neuropharmacology 28:855– 861.
Tohgi H, Utsugisawa K, Yoshimura M, Nagane Y, Mihara M
(1998): Age-related changes in nicotinic acetylcholine receptor subunits alpha4 and beta2 messenger RNA expression in
postmortem human frontal cortex and hippocampus. Neurosci
Lett 245:139 –142.
Ulrich J, Johannson-Locher G, Seiler WO, Stahelin HB (1997):
Does smoking protect from Alzheimer’s disease? Alzheimertype changes in 301 unselected brains from patients with
known smoking history. Acta Neuropathol 94:450 – 454.
Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J,
Swanson LW (1989): Distribution of alpha 2, alpha 3, alpha
4 and beta 2 neuronal nicotinic receptor subunit mRNAs in

184

BIOL PSYCHIATRY
2001;49:175–184

the central nervous system: A hybridization histochemical
study in the rat. J Comp Neurol 284:314 –335.
Wang H, Lee D, D’Andrea M, Peterson P, Shank R, Reitz A
(2000): Beta-amyloid (1-42) binds to alpha nicotinic acetylcholine receptor with high affinity: Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626 –5632.
Warpman U, Nordberg A (1995): Epibatidine and ABT 418
reveal selective losses of alpha 4 beta 2 nicotinic receptors in
Alzheimer brains. Neuroreport 6:2419 –2423.
Wenk GL, Rokaeus A (1988): Basal forebrain lesions differentially alter galanin levels and acetylcholinergic receptors in
the hippocampus and neocortex. Brain Res 460:17–21.
Wevers A, Jeske A, Lobron C, Birtsch C, Heinemann S,
Maelicke A, et al (1994): Cellular distribution of nicotinic
acetylcholine receptor subunit mRNAs in the human cerebral
cortex as revealed by non-isotopic in situ hybridization. Brain
Res Mol Brain Res 25:122–128.
Wevers A, Monteggia L, Nowacki S, Bloch W, Schu¨tz U,
Lindstrom J, et al (1999): Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer’s

J. Court et al

disease-histotopographical correlation with amyloid plaques
and hyperphosphorylated tau-protein. Eur J Neurosci 11:
2551–2565.
Wilkie GI, Hutson P, Sullivan JP, Wonnacott S (1996): Pharmacological characterization of a nicotinic autoreceptor in rat
hippocampal synaptosomes. Neurochem Res 21:1141–1148.
Wonnacott S (1997): Presynaptic nicotinic ACh receptors.
Trends Neurosci 20:92–98.
Xuereb JH, Perry EK, Candy JM, Bonham JR, Perry RH,
Marshall E (1990): Parameters of cholinergic neurotransmission in the thalamus in Parkinson’s disease and Alzheimer’s
disease. J Neurol Sci 99:185–197.
Zoli M, Lena C, Picciotto M, Changeux J-P (1998): Identification of four classes of brain nicotinic receptors using beta2
mutant mice. J Neurosci 18:4461– 4472.
Zoli M, Picciotto MR, Ferrari R, Cocchi D, Changeux J-P
(1999): Increased neurodegeneration during ageing in mice
lacking high-affinity nicotine receptors. EMBO J 18:1235–
1244.