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International Journal of Alzheimer's Disease
Volume 2010 (2010), Article ID 548913, 11 pages
http://dx.doi.org/10.4061/2010/548913
Review Article

Brain Imaging of Nicotinic Receptors in Alzheimer's Disease

Division of Clinical Neuroscience, Center for Forensic Mental Health, Chiba University, 1-8-1 Inohana Chiba 260-8670, Japan

Received 30 October 2010; Accepted 8 December 2010

Academic Editor: Adam S. Fleisher

Copyright © 2010 Jin Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels which are widely distributed in the human brain. Several lines of evidence suggest that two major subtypes (α4β2 and α7) of nAChRs play an important role in the pathophysiology of Alzheimer's disease (AD). Postmortem studies demonstrated alterations in the density of these subtypes of nAChRs in the brain of patients with AD. Currently, nAChRs are one of the most attractive therapeutic targets for AD. Therefore, several researchers have made an effort to develop novel radioligands that can be used to study quantitatively the distribution of these two subtypes in the human brain with positron emission tomography (PET) and single-photon emission computed tomography (SPECT). In this paper, we discuss the current topics on in vivo imaging of two subtypes of nAChRs in the brain of patients with AD.

1. Introduction

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly and has become a major worldwide health problem. Several reports indicated that it is affecting almost 1 in 10 individuals over the age of 65 [1], and as life expectancy increases, over 37 million people suffer with AD, and it is projected to quadruple by 2050 [2]. AD accounts for over 50% of senile dementia and the majority of presenile dementia cases and is characterized by progressive deterioration of higher cognitive functions including the loss of memory [3, 4].

van Duijn and Hofman [5] reported the inverse relationship between smoking history and early onset AD, suggesting that smoking may protect against AD [6]. Furthermore, Rusted and Trawley [7] reported acute improvements in prospective memory following nicotine administration. Although Swan and Lessov-Schlaggar [8] discuss the effects of tobacco smoke and nicotine on cognition in their review, smoking is associated with increased risk for negative preclinical and cognitive outcomes in younger people as well as in older adults. More recently, a meta-analysis including longitudinal studies published between 1995 and 2007 reported that current smokers relative to never-smokers were at increased risk of AD, vascular dementia, any dementia, and cognitive decline, in over the age of 65 [9]. Several lines of evidence demonstrated that smoking almost doubled the risk of AD and that smoking cessation might contribute to a reduction of risk factors for AD and cardiovascular disease [10, 11]. Noteworthy, the later is also known as a risk factor for AD. These results suggest that smoking cessation may play an important role in not only primary but also secondary prevention of AD. In contrast, although the discussion about neuroprotection by smoking has been continued, it is possible that nicotinic acetylcholine receptors (nAChRs) in the brain might play a role in the pathophysiology of AD.

The nAChRs are one of the main classes of AChRs, which have a pentameric structure composed of five membrane spanning subunits, of which nine different types have thus far been identified and cloned. To date, twelve neuronal nAChR subunits have been described [12]; nine (α2–α10) code for subunits [12] based on the presence of adjacent cysteine residues in the predicted protein sequences, in a region homologous to the putative agonist-binding site of the muscle, a subunit (α1) and three referred to as non-α or β-subunits (β2–β4). Among the several nAChR subtypes in the human central nervous system (CNS), the heteromeric α4β2 and homomeric α7 subtypes (Figure 1) are predominant in the brain [13, 14]. It has been reported that other subtypes (e.g., α3, α6) exist in the brain [15, 16] and that α6 subtype might be mainly involved in the pathophysiology of Parkinson's disease [16]. Furthermore, studies using postmortem human brain samples have demonstrated alterations in the levels of α4 and α7 nAChR in the brains of patients with AD [15, 1719]. Despite its lower number, loss of α3 subtype consistent with α4 and α7 nAChR subtypes was also observed in the brains of patients with AD [15]. Taken together, it is likely that these two subtypes (α4β2 and α7) of nAChR might play a role in the pathogenesis of AD. Therefore, it is of great interest to examine whether these two subtypes of nAChR are altered in the living brain of patients with AD using brain imaging techniques.

fig1
Figure 1: Structures of α4β2 nAChR (a) and α7 nAChR (b).

In this paper, we discuss the recent findings on imaging of these two nAChRs (α4β2 and α7) in the brain with AD using positron emission tomography (PET) and single-photon emission computed tomography (SPECT).

2. α4β2 nAChRs Subtype

2.1. Relationship between Amyloid-β and α4β2 nAChR

Amyloid β protein (Aβ) is a major constituent of senile plaques and one of the candidates for the cause of the neurodegeneration found in AD. It has been shown that the accumulation of Aβ precedes other pathological changes and causes neurodegeneration or neuronal death in vitro and in vivo [20, 21]. The loss of memory seen in AD is thought to be associated with Aβ-induced impairment of synaptic plasticity such as long-term potentiation (LTP) in the hippocampus. There are lines of evidence suggesting that nAChR activation provides protection against Aβ-induced neurotoxicity in cultured cortical neurons [22, 23]. These results indicated that nicotine protects against Aβ-induced neuronal death, and similar effect has been also observed in those selective α4β2 nAChR agonists such as cytosine and epibatidine, but this neuroprotection is blocked by the selective α4β2 nAChR antagonist dihydro-β-erythroidine (DHβE). Moreover, recently, Wu et al. [24] investigated a possible role of α4β2 nAChR in mediating the impairment of long-term potentiation (LTP) by various forms of Aβ in in vivo. They reported that intracerebroventricular injection of Aβ40, Aβ25–35, or Aβ31–35 significantly suppressed high-frequency stimulation-induced LTP. Similarly, epibatidine dose dependently suppressed the induction of LTP. Whereas DHβE showed no effect on the induction of LTP, it significantly reversed Aβ31–35-induced LTP impairment. These findings suggest that α4β2 nAChR, which can be directly activated by Aβ, is required for Aβ suppression of LTP in vivo. The mechanisms by which nicotine enhanced the inhibition of LTP by Aβ were not clear. A possible explanation is that nicotine could activate nAChRs present in inhibitory interneurons, thereby potentiating inhibitory inputs to hippocampal neurons.

2.2. Cognition and α4β2 nAChR Agonists

It is likely that reduced density of nAChR is related to dementia severity, assessed using a global rating. Nicotine has been postulated to be a possible treatment for AD, improving cognition in humans [25]. Recently, Loughead et al. [26] reported novel evidence that the α4β2 partial agonist varenicline increased working memory-related brain activity after 3 days of nicotine abstinence, particularly at high levels of task difficulty, with associated improvements in cognitive performance among highly dependent smokers.

2.3. Postmortem Studies of α4β2 nAChR in the Brain of Patients with AD

Not only transmitter release but also receptor-binding sites may be altered in the brain of AD patients [2729]. Postmortem studies showed the reduction (up to 50%) of α4β2 subtype of nAChRs in brain of patients with AD [30], and it may occur very early in the course of AD [31]. Both α4 and α7 subunits are known to be important constituents in α4β2 and α7 receptor subtypes, respectively. Investigation using the autopsy samples of human cerebral cortex has clearly shown that these two subtypes (α4 and α7 isoforms) are significantly decreased in their protein amount in the cortices of AD patients [15, 19, 32].

2.4. Imaging of α4β2 nAChR Subtype

Considering the role of α4β2 nAChR in the pathophysiology of AD, it is of great interest to study α4β2 nAChR in the living human brain using PET/SPECT. Much effort has been devoted to visualize α4β2 nAChR in the brain by PET/SPECT. Currently, two PET ligands, including [11C]nicotine and 2-[18F]fluoro-3-(2 (S)azetidinylmethoxy)pyridine (2-[18F]F-A-85380), and a SPECT ligand, 5-[123I]iodo-3-(2 (S)-2-azetidinylmethoxy)pyridine (5-[123I]I-A-85380), (Figure 2) for in vivo imaging of α4β2 nAChR in the human brain have been used in clinical studies [3335].

548913.fig.002
Figure 2: Chemical structures of radioligands for nAChRs.
2.5. [11C]Nicotine

The development of radiolabelled nicotine [36, 37] has allowed for evaluating the uptake and distribution of nAChR in the living human brain [3840]. The data obtained by [11C]nicotine is generally consistent with the known pattern of nAChR measured by in vitro binding in autopsy brain tissue [39]. [11C]nicotine-PET has been used to study α4β2 nAChR in human brain, and a severe loss of the nAChR has been detected in the brain of patients with AD [13]. Cortical nAChRs in mild AD patients are robustly associated with the cognitive function of attention [35] and have revealed a significant negative correlation between severity of cognitive impairment and density of brain nAChR [40]. It will be, therefore, of interest to study an alteration in α4β2 nAChR at a presymptomatic stage of AD. Furthermore, the in vivo cortical AChE inhibition and [11C]nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory when administering galantamine [41]. Thus, [11C]nicotine-PET may be also used for monitoring treatment efficacy in AD patients [41, 42].

Unfortunately, [11C]nicotine displays high levels of nonspecific binding, rapid metabolism, and rapid washout of the brain [43]. The heterogeneity of [11C]nicotine binding in the brain also precludes the identification of a reference region which may be used to accurately determine nonspecific binding. Taken together, it is unlikely that [11C]nicotine might be a suitable PET ligand for in vivo imaging of α4β2 nAChR in human brain.

2.6. 2-[18F]F-A-85380 and 5-[123I]I-A-85380

A-85380 [3-(2(S)-azetidinylmethoxy) pyridine] is a potent and selective agonist with high affinity for α4β2 nAChR subtype and low affinity for other nAChR subtypes [44]. A-85380 is effective in a wide range of preclinical models of CNS disorders [45, 46]. Recently, A-85380 was successfully labeled using 18F or 125/123I with a high affinity (  pM for F and  pM for I) for α4β2 nAChR [44, 47, 48]. These radioligands have been evaluated in vitro and in vivo as PET/SPECT radioligands to visualize α4β2 nAChR subtype in the brain [49, 50]. In healthy nonsmoking human brain, both 2-[18F]F-A85380 and 5-[123I]I-A85380 have revealed a pattern of highest uptake in the thalamus, intermediate in the midbrain, pons, cerebellum, and cortex, and lowest in white matter [5052], which is consistent with the regional distribution of α4β2 nAChR.

Furthermore, a study of age-related decline in nicotinic receptor availability showed that regional β2 nAChR availability were inversely correlated with decline ranging from 32% (thalamus) to 18% (occipital cortex) over the adult lifespan, or up to 5% per decade [53]. These results may corroborate postmortem reports of decline in high-affinity nicotine binding with age and may aid in elucidating the role of β2-nAChR in cognitive aging. In addition, 2-[18F]F-A-85380 or 5-[123I]I-A-85380 have been used to evaluate the effect of smoking on occupancy of α4β2 nAChR [54, 55]. Smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of α4β2 nAChR for 3.1 hours after smoking. Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving. The extent of receptor occupancy found herein suggests that smoking may lead to withdrawal alleviation by maintaining nAChR in the desensitized state.

Both 2-[18F]F-A-85380 and 5-[123I]I-A-85380 have been used in AD patients [51, 5660]. In 17 patients with moderate to severe AD and 6 subjects with amnestic mild cognitive impairment (MCI) compared with 10 healthy control subjects, Sabri et al. [56] found significant reductions of α4β2 nAChR in brain regions (hippocampus, caudate, frontal cortex, temporal cortex, posterior cingulate, anterior cingulate, and parietal cortex) in the brain of AD by using 2-[18F]F-A-85380. Most recently, Kendziorra et al. [57] reported that both patients with AD and those with MCI showed a significant reduction in 2-[18F]F-A-85380 binding potential in typical AD-affected brain regions and that the 2-[18F]F-A-85380 binding potential correlated with the severity of cognitive impairment. In addition, only MCI patients who converted to AD in the later course had a reduction in 2-[18F]F-A-85380 binding potential. Thus, it is likely that 2-[18F]F-A-85380 PET might give prognostic information about a conversion from MCI to AD. Similar findings were also reported by 5-[123I]I-A-85380, showing significant reductions in the activity ratios of the region of interest to cerebellum in the frontal, striatal, right medial temporal, and pontine regions in 16 patients with AD compared with 16 healthy control subjects [59] (Figure 3). These findings suggest that a reduction in α4β2 nAChR occurs during symptomatic stages of AD and that the α4β2 nAChR availability in these regions correlated with the severity of cognitive impairment. In contrast, there were no differences in distribution volume (DV) of nAChR between the healthy controls and early AD patients (Figure 4) [51, 58].

548913.fig.003
Figure 3: Comparison with regional uptake values of 5-[123I]I-A85380 in age-matched healthy control and patients with Alzheimer’s disease. Significant bilateral reductions in nicotinic receptor binding were identified in frontal, striatal, right medial temporal, and pons in patients with AD compared to controls. (Data is from the paper of O'Brien et al. [59].) , , .
548913.fig.004
Figure 4: Regional α4β2-nAChR availability of 5-[123I]I-A85380 in age-matched healthy control (HC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) groups. No significant regional differences among the subject groups for any of the 8 regions, including the 4 neocortical regions, were identified. (Data is from the paper of Mitsis et al. [58].)

2-[18F]F-A-85380 PET has been used to observe outcome of drug treatment for the improvements of cognition in patients with mild AD [61]. However, no significant correlations were found between cognitive measures and nAChR simplified DV (Figure 5). These results are similar to the results reported by Kadir et al. [41] in their studies using [11C]nicotine. The relationship between cognition in AD and cholinergic dysfunction may be related to a number of factors, including the degree of cholinergic system (or receptor) loss, the other nAChR subtypes, or other neurochemical systems.

548913.fig.005
Figure 5: Regional nAChR simplified distribution volume (DV(s)) of 2-[18F]F-A85380 in healthy control (HC) and Alzheimer’s disease (AD) groups. No significant difference in nAChR DV(s) was found between both groups. (Data is from the paper of Ellis et al. [51].)

3. α7 nAChR Subtype

3.1. Relationship between Aβ and α7 nAChR

Of the two major subtypes of nAChRs in the CNS, α7 subtype has lower affinity for ACh compared to α4β2 subtype [62]. Accumulating evidence suggests that α7 nAChR plays a role in the pathophysiology of AD. Aβ has picomolar affinity for α7 nAChR [63, 64], which results in the formation of Aβ-α7 nAChR complex. This complex is known to move intracellularly and cause neurotoxicity [6365]. Interestingly, this neurotoxicity is not present in transgenic mouse model of AD overexpressing a mutated form of the human amyloid precursor protein (APP) and lacking the α7 nAChR [66]. Recently, Bencherif and Lippiello [67] pointed out that the α7-JAK2-(NF-κB; STAT3)-Bcl2 prosurvival pathway is important for the neuroprotective role of α7 nAChR (Figure 6). By blocking cytosolic cytochrome C, which is released from the mitochondria via Aβ1–42, Bcl2 fully counteracts the Aβ1–42-induced apoptosis of cells [68]. The fact that this antiapoptotic pathway is further related with ApoE4 [69], GSK-3β-activated tau phosphorylation [70], and Wnt signaling pathways [71] denotes the critical role of α7 nAChR in pathophysiology of AD.

548913.fig.006
Figure 6: Schematic representation of neuroprotective role of α7 nAChR.

The 3xTg-AD mice [72], which are triple transgenic mice expressing APP, presinilin-1, and Tau, were shown to have an age-dependent reduction of α7 nAChR. This reduction was limited to brain regions where intraneuronal Aβ42 accumulation occurred [73]. The early cognitive deficits of 3xTG-AD mice also correlate with intracellular Aβ accumulation, and the clearing of this Aβ accumulation by immunotherapy reverses the early cognitive impairment [74].

Tg2576 transgenic mice (APPswe) dramatically reduced Aβ plaque expression with chronic administration of nicotine for 5.5 months [75]. It is further reported that a 10-day administration of nicotine reduced the guanidinium-soluble Aβ levels by 46 to 66%, whereas the intracellular Aβ levels remained unchanged [76]. This treatment with nicotine also resulted in less glial fibrillary acidic protein- (GFAP-) immunoreactive astrocytes around the amyloid plaques and increased numbers of α7 nAChR in the cortex of APPswe mice [76]. Bencherif [68] points out the importance of these data, as reduction of Aβ with anti-Aβ antibody treatment is reported to rapidly recover the associated neuritic dystrophy in living animals [77].

Orr-Urtreger et al. [78] generated α7 nAChR gene knock-out (KO) mice, and the resulting α7 nAChR KO mice did not show any morphological central nervous system abnormalities [78, 79], but behavioral tests point out some cognitive deficits in KO mice, such as impaired sustained attention [80, 81], impairment in working memory [82], and impairment in performance under high attentional demand [83]. The cognitive deficits seen in APP transgenic mice worsen when α7 nAChR is absent at the same time [84]. These α7 nAChR KO APP mice showed significant reduction in hippocampal and basal forebrain choline acetyltransferase activity and loss of hippocampal neurons and markers; stereological analyses indicated more pronounced loss of hippocampal pyramidal neurons and volume loss compared with APP mice [84]. Taken all together, it is likely that α7 nAChR might play an important role in the process of Aβ disposition which was detected in the brain of patients with AD.

3.2. Cognition and α7 nAChR Agonists

A number of α7 nAChR agonists are reported to improve recognition memory in rodents. These agonists include tropisetron [85], ABBF [86], AR-R 17779 [87], SSR180711 [88, 89], A-582941 [90], and SEN123333 [91]. In nonhuman primates, improvements in long-delay performance of delayed matching tasks are reported by α7 nAChR agonists GTS-21 [92] and A-582941 [93].

It is reported that nicotine inhibits Aβ deposition and aggregation in the cortex and hippocampus of APP transgenic mice [94]. RNA interference experiments indicated that these nicotine-mediated effects require α7 nAChR. In another study [70], the selective α7 nAChR agonist A-582941 led to increased phosphorylation of the inhibitory regulating amino acid residue Ser-9 on glycogen synthase kinase 3β (GSK3β), a major kinase responsible for tau hyperphosphorylation in AD neuropathology. This was observed in mouse cingulate cortex and hippocampus and was not observed in α7 nAChR KO mice. S9-GSK3β phosphorylation was also seen in the hippocampus of Tg2576 (APP), as well as wild-type mice by steady-state exposure of A-582941. Moreover, continuous infusions of A-582941 decreased phosphorylation of tau in hippocampal CA3 Mossy fibers in a hypothermia-induced tau hyperphosphorylation mouse model and also decreased spinal motoneurons in AD double transgenic APP/tau mouse line. This group points out that α7 nAChR agonists may have therapeutic potential through GSK3β inhibition followed by reduction of tau hyperphosphorylation and further suggest that this pharmacology may have the potential to provide disease modifying benefit in the treatment of AD.

It is reported that the α7 nAChR agonist GTS-21 prevented Aβ25–35-induced impairment of acquisition performance and probe trail test in Morris water maze [95]. Their study showed first in vivo evidence that treatment with GTS-21 ameliorates the Aβ-induced deficit in spatial cognition through not only activating α7 nAChR but also preventing the Aβ-impaired α7 nAChR.

Using a novel selective α7 nAChR partial agonist S 24795, Wang et al. [96] showed that, in contrast to anti-AD drugs, galantamine (a cholinesterase inhibitor) and memantine (an N-methyl-D-aspartate (NMDA) receptor antagonist), S 24795 reduced or limited Aβ42-α7 nAChR association, Aβ42-induced tau phosphorylation, Aβ42 accumulations, and Aβ42-mediated inhibition of α7 nAChR Ca2+ influx in rodent brain [96]. S 24795 more importantly restored α7 nAChR functional deficits which had resulted from continued exposure to exogenous Aβ42.

Taken all together, α7 nAChR is one of the therapeutic targets for AD [97, 98].

3.3. Postmortem Studies of α7 nAChR in the Brain of Patients with AD

In the postmortem brain of patients with AD, decline of α7 nAChR appears early in the disease and was associated with the progression of cognitive deficits [99101]. Although the protein levels are reduced in the cortex and hippocampus of AD patients [15, 19, 32, 100, 102], contradictions arise at the level of gene transcription. For example, levels of α7 nAChR protein were reduced by 36% in the hippocampus of AD patients [15], but α7 nAChR mRNA expression is increased by 65% [18]. Furthermore, no differences in [125I]α-bungarotoxin binding were found in the frontal cortex of AD patients [103] and negative reduction of the α7 nAChR protein levels [104].

3.4. Imaging of α7 nAChR in the Brain

Given the role of α7 nAChR in the pathogenesis of AD, it is of great interest to study α7 nAChR in the living human brain using PET/SPECT. Much effort has been devoted to visualize α7 nAChR in the brain by PET/SPECT, but the development of a radioligand that depicts α7 nAChR specifically has been problematic due to its relatively low amount in the brain [105108]. Generally, α-bungarotoxin and MLA are well known as specific α7 nAChR antagonists. However, due to their large molecular weights, they have difficulty passing through the blood-brain barrier which makes them unfavorable for radioligands [109111]. Consequently, a number of radioligands for α7 nAChR are being developed and evaluated as PET/SPECT radioligand. However, all radioligands except [11C]CHIBA-1001 were unsuccessful [112].

3.5. [11C]CHIBA-1001 as a Novel PET Ligand for α7 nAChR

We developed a novel PET ligand, 4-[11C]methylphenyl 1,4-diazabicyclo[3.2.2.]nonane-4-carboxylate ([11C]CHIBA-1001) (Figure 7). A PET study using conscious monkeys demonstrated that the distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective α7 nAChR agonist SSR180711 (5.0 mg/kg), but not the selective α4β2 nAChR agonist A85380 (1.0 mg/kg) [89]. In addition, we reported that the order of drugs for the inhibition of [3H]CHIBA-1001 binding to rat brain membranes was similar to α7 nAChR pharmacological profiles [113]. We also reported a preliminary PET study of [11C]CHIBA-1001 in a healthy human [114, 115]. Very recently, we reported that [125I]CHIBA-1006, an iodine derivative of SSR180711, has a high affinity for α7 nAChR as compared with CHIBA-1001 [116]. Considering the good brain permeability of derivatives (e.g., SSR180711 and CHIBA-1001) of CHIBA-1006, it would be of great interest to examine whether [123I]CHIBA-1006 and [124I]CHIBA-1006 are suitable radioligands for in vivo labeling of α7 nAChRs in the brain using SPECT and PET, respectively [116].

548913.fig.007
Figure 7: Chemical structure of [11C]CHIBA-1001.

At present, [11C]CHIBA-1001 is the only PET ligand which can be available for in vivo study of α7 nAChRs in intact human brain [114]. PET studies of [11C]CHIBA-1001 in patients with AD are currently underway with [11C]Pittsburgh compound D ([11C]PiB)-PET and [18F]fluorodeoxyglucose ([18F]FDG)-PET. This study aims to evaluate the relationship between the distribution of α7 nAChR (assessed by [11C]CHIBA-1001) and Aβ disposition (assessed by [11C]PiB), while estimating the stage and cognitive levels (assessed by [18F]FDG-PET and neuropsychological examinations) for each AD patient.

4. Conclusions

Considering the importance of early prevention of onset of AD, it is very important to detect alternations in nAChRs at the presymptomatic stage of AD. In patients with MCI, the early detection and early therapeutic intervention would be beneficial. Therefore, brain imaging of nAChRs using PET and SPECT will be a powerful tool to study the mechanisms underlying pathological brain processes of cognitive disturbances in these patients. Currently, some PET and SPECT ligands for both subtypes (α4β2 nAChR and α7 nAChR) have been used to investigate the changes in receptor densities and functions of patients with AD. Gaining a better understanding of the role of nAChRs in the pathophysiology of AD is expected to provide new perspectives for treating this disorder.

Conflict of Interests

The authors have no conflict of interests.

Abbreviations

AD:Alzheimer’s disease
DV:Distribution volume
GFAP:Glial fibrillary acidic protein
LTP:Long-term potentiation
nAChR:Nicotinic acetylcholine receptor
PET:Positron emission tomography
SPECT:Single-photon emission tomography.

Acknowledgments

This study was supported in part by a grant from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation of Japan (Grant ID: 06-46, to K. Hashimoto). The authors would like to thank their collaborators who are listed as the coauthors of their papers in the reference list.

References

  1. D. A. Evans, H. H. Funkenstein, M. S. Albert et al., “Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported,” Journal of the American Medical Association, vol. 262, no. 18, pp. 2551–2556, 1989. View at Google Scholar · View at Scopus
  2. R. Brookmeyer, E. Johnson, K. Ziegler-Graham, and H. M. Arrighi, “Forecasting the global burden of Alzheimer's disease,” Alzheimer's and Dementia, vol. 3, no. 3, pp. 186–191, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. J. N. Octave, “The amyloid peptide and its precursor in Alzheimer's disease,” Reviews in the Neurosciences, vol. 6, no. 4, pp. 287–316, 1995. View at Google Scholar · View at Scopus
  4. E. Grober, C. B. Hall, R. B. Lipton, A. B. Zonderman, S. M. Resnick, and C. Kawas, “Memory impairment, executive dysfunction, and intellectual decline in preclinical Alzheimer's disease,” Journal of the International Neuropsychological Society, vol. 14, no. 2, pp. 266–278, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. C. M. van Duijn and A. Hofman, “Relation between nicotine intake and Alzheimer's disease,” British Medical Journal, vol. 302, no. 6791, pp. 1491–1494, 1991. View at Google Scholar · View at Scopus
  6. A. B. Graves, C. M. van Duijn, V. Chandra et al., “Alcohol and tobacco consumption as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies,” International Journal of Epidemiology, vol. 20, supplement 2, pp. S48–S57, 1991. View at Google Scholar
  7. J. M. Rusted and S. Trawley, “Comparable effects of nicotine in smokers and nonsmokers on a prospective memory task,” Neuropsychopharmacology, vol. 31, no. 7, pp. 1545–1549, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. G. E. Swan and C. N. Lessov-Schlaggar, “The effects of tobacco smoke and nicotine on cognition and the brain,” Neuropsychology Review, vol. 17, no. 3, pp. 259–273, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. R. Peters, R. Poulter, J. Warner, N. Beckett, L. Burch, and C. Bulpitt, “Smoking, dementia and cognitive decline in the elderly, a systematic review,” BMC Geriatrics, vol. 8, article 36, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. J. K. Cataldo, J. J. Prochaska, and S. A. Glantz, “Cigarette smoking is a risk factor for Alzheimer's disease: an analysis controlling for tobacco industry affiliation,” Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 465–480, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. J. K. Cataldo and S. A. Glantz, “Smoking cessation and Alzheimer's disease: facts, fallacies and promise,” Expert Review of Neurotherapeutics, vol. 10, no. 5, pp. 629–631, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. C. Gotti, M. Zoli, and F. Clementi, “Brain nicotinic acetylcholine receptors: native subtypes and their relevance,” Trends in Pharmacological Sciences, vol. 27, no. 9, pp. 482–491, 2006. View at Publisher · View at Google Scholar
  13. D. Paterson and A. Nordberg, “Neuronal nicotinic receptors in the human brain,” Progress in Neurobiology, vol. 61, no. 1, pp. 75–111, 2000. View at Publisher · View at Google Scholar · View at Scopus
  14. J. A. Dani and D. Bertrand, “Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system,” Annual Review of Pharmacology and Toxicology, vol. 47, pp. 699–729, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. Z. Z. Guan, X. Zhang, R. Ravid, and A. Nordberg, “Decreased protein levels of nicotinic receptor subunits in the hippocampus and temporal cortex of patients with Alzheimer's disease,” Journal of Neurochemistry, vol. 74, no. 1, pp. 237–243, 2000. View at Publisher · View at Google Scholar · View at Scopus
  16. X. A. Perez, T. Bordia, J. M. McIntosh, and M. Quik, “α6β2* and α4β2* nicotinic receptors both regulate dopamine signaling with increased nigrostriatal damage: relevance to Parkinson's disease,” Molecular Pharmacology, vol. 78, no. 5, pp. 971–980, 2010. View at Publisher · View at Google Scholar
  17. E. K. Perry, C. M. Morris, J. A. Court et al., “Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology,” Neuroscience, vol. 64, no. 2, pp. 385–395, 1995. View at Publisher · View at Google Scholar
  18. E. Hellström-Lindahl, M. Mousavi, X. Zhang, R. Ravid, and A. Nordberg, “Regional distribution of nicotinic receptor subunit mRNAs in human brain: comparison between Alzheimer and normal brain,” Molecular Brain Research, vol. 66, no. 1-2, pp. 94–103, 1999. View at Publisher · View at Google Scholar · View at Scopus
  19. L. Burghaus, U. Schütz, U. Krempel et al., “Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients,” Molecular Brain Research, vol. 76, no. 2, pp. 385–388, 2000. View at Publisher · View at Google Scholar · View at Scopus
  20. B. A. Yankner, L. K. Duffy, and D. A. Kirschner, “Neurotrophic and neurotoxic effects of amyloid β protein: reversal by tachykinin neuropeptides,” Science, vol. 250, no. 4978, pp. 279–282, 1990. View at Google Scholar · View at Scopus
  21. N. W. Kowall, M. F. Beal, J. Busciglio, L. K. Duffy, and B. A. Yankner, “An in vivo model for the neurodegenerative effects of β amyloid and protection by substance P,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 16, pp. 7247–7251, 1991. View at Google Scholar · View at Scopus
  22. T. Kihara, S. Shimohama, M. Urushitani et al., “Stimulation of α4β2 nicotinic acetylcholine receptors inhibits β- amyloid toxicity,” Brain Research, vol. 792, no. 2, pp. 331–334, 1998. View at Publisher · View at Google Scholar · View at Scopus
  23. W. Fu and J. H. Jhamandas, “β-amyloid peptide activates non-α7 nicotinic acetylcholine receptors in rat basal forebrain neurons,” Journal of Neurophysiology, vol. 90, no. 5, pp. 3130–3136, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. M. N. Wu, Y. X. He, F. Guo, and J. S. Qi, “α4β2 nicotinic acetylcholine receptors are required for the amyloid β protein-induced suppression of long-term potentiation in rat hippocampal CA1 region in vivo,” Brain Research Bulletin, vol. 77, no. 2-3, pp. 84–90, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. P. A. Newhouse, A. Potter, and A. Singh, “Effects of nicotinic stimulation on cognitive performance,” Current Opinion in Pharmacology, vol. 4, no. 1, pp. 36–46, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Loughead, R. Ray, E. P. Wileyto et al., “Effects of the α4β2 partial agonist varenicline on brain activity and working memory in abstinent smokers,” Biological Psychiatry, vol. 67, no. 8, pp. 715–721, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. D. D. Flynn and D. C. Mash, “Characterization of L-[3H]nicotine binding in human cerebral cortex: comparison between Alzheimer's disease and the normal,” Journal of Neurochemistry, vol. 47, no. 6, pp. 1948–1954, 1986. View at Google Scholar · View at Scopus
  28. P. J. Whitehouse, A. M. Martino, P. G. Antuono et al., “Nicotinic acetylcholine binding sites in Alzheimer's disease,” Brain Research, vol. 371, no. 1, pp. 146–151, 1986. View at Google Scholar
  29. P. J. Whitehouse, A. M. Martino, M. V. Wagster et al., “Reductions in [3H]nicotinic acetylcholine binding in Alzheimer's disease and Parkinson's disease: an autoradiographic study,” Neurology, vol. 38, no. 5, pp. 720–723, 1988. View at Google Scholar · View at Scopus
  30. U. Warpman and A. Nordberg, “Epibatidine and ABT 418 reveal selective losses of α4β2 nicotinic receptors in Alzheimer brains,” NeuroReport, vol. 6, no. 17, pp. 2419–2423, 1995. View at Google Scholar · View at Scopus
  31. A. Marutle, U. Warpman, N. Bogdanovic, L. Lannfelt, and A. Nordberg, “Neuronal nicotinic receptor deficits in Alzheimer patients with the Swedish amyloid precursor protein 670/671 mutation,” Journal of Neurochemistry, vol. 72, no. 3, pp. 1161–1169, 1999. View at Publisher · View at Google Scholar · View at Scopus
  32. A. Wevers, L. Burghaus, N. Moser et al., “Expression of nicotinic acetylcholine receptors in Alzheimer's disease: postmortem investigations and experimental approaches,” Behavioural Brain Research, vol. 113, no. 1-2, pp. 207–215, 2000. View at Publisher · View at Google Scholar · View at Scopus
  33. J. D. Gallezot, M. Bottlaender, M. C. Grégoire et al., “in vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET,” Journal of Nuclear Medicine, vol. 46, no. 2, pp. 240–247, 2005. View at Google Scholar · View at Scopus
  34. A. L. Brody, M. A. Mandelkern, E. D. London et al., “Cigarette smoking saturates brain α4β2 nicotinic acetylcholine receptors,” Archives of General Psychiatry, vol. 63, no. 8, pp. 907–915, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. A. Kadir, O. Almkvist, A. Wall, B. Långström, and A. Nordberg, “PET imaging of cortical C-nicotine binding correlates with the cognitive function of attention in Alzheimer's disease,” Psychopharmacology, vol. 188, no. 4, pp. 509–520, 2006. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Maziere, D. Comar, C. Marazano, and G. Berger, “Nicotine 11C: synthesis and distribution kinetics in animals,” European Journal of Nuclear Medicine, vol. 1, no. 4, pp. 255–258, 1976. View at Google Scholar · View at Scopus
  37. C. Halldin, K. Nagren, C. G. Swahn, B. Langstrom, and H. Nyback, “(S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET,” International Journal of Radiation Applications and Instrumentation B, vol. 19, no. 8, pp. 871–880, 1992. View at Publisher · View at Google Scholar · View at Scopus
  38. H. Nyback, A. Nordberg, B. Langstrom et al., “Attempts to visualize nicotinic receptors in the brain of monkey and man by positron emission tomography,” Progress in Brain Research, vol. 79, pp. 313–319, 1989. View at Google Scholar · View at Scopus
  39. A. Nordberg, L. Nilsson-Hakansson, A. Adem et al., “The role of nicotinic receptors in the pathophysiology of Alzheimer's disease,” Progress in Brain Research, vol. 79, pp. 353–362, 1989. View at Google Scholar · View at Scopus
  40. A. Nordberg, H. Lundqvist, P. Hartvig, A. Lilja, and B. Langstrom, “Kinetic analysis of regional (S)(-)11C-nicotine binding in normal and Alzheimer brains—in vivo assessment using positron emission tomography,” Alzheimer Disease and Associated Disorders, vol. 9, no. 1, pp. 21–27, 1995. View at Google Scholar · View at Scopus
  41. A. Kadir, T. Darreh-Shori, O. Almkvist et al., “PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD,” Neurobiology of Aging, vol. 29, no. 8, pp. 1204–1217, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. A. Nordberg, H. Lundqvist, P. Hartvig et al., “Imaging of nicotinic and muscarinic receptors in Alzheimer's disease: effect of tacrine treatment,” Dementia and Geriatric Cognitive Disorders, vol. 8, no. 2, pp. 78–84, 1997. View at Google Scholar
  43. F. Grunwald, H. J. Biersack, W. Kuschinsky, D. Sorger, I. Kampfer, and W. H. Knapp, “Nicotine receptor mapping,” European Journal of Nuclear Medicine, vol. 23, no. 8, pp. 1012–1014, 1996. View at Google Scholar · View at Scopus
  44. J. P. Sullivan, D. Donnelly-Roberts, C. A. Briggs et al., “A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity α4β2 nicotinic acetylcholine receptor ligand,” Neuropharmacology, vol. 35, no. 6, pp. 725–734, 1996. View at Publisher · View at Google Scholar · View at Scopus
  45. L. E. Rueter, M. D. Meyer, and M. W. Decker, “Spinal mechanisms underlying A-85380-induced effects on acute thermal pain,” Brain Research, vol. 872, no. 1-2, pp. 93–101, 2000. View at Publisher · View at Google Scholar · View at Scopus
  46. M. J. Buckley, C. Surowy, M. Meyer, and P. Curzon, “Mechanism of action of A-85380 in an animal model of depression,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 28, no. 4, pp. 723–730, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. L. E. Rueter, D. L. Donnelly-Roberts, P. Curzon, C. A. Briggs, D. J. Anderson, and R. S. Bitner, “A-85380: a pharmacological probe for the preclinical and clinical investigation of the αβ neuronal nicotinic acetylcholine receptor,” CNS Drug Reviews, vol. 12, no. 2, pp. 100–112, 2006. View at Publisher · View at Google Scholar · View at Scopus
  48. A. G. Mukhin, D. Gündisch, A. G. Horti et al., “5-iodo-a-85380, an α4β2 subtype-selective ligand for nicotinic acetylcholine receptors,” Molecular Pharmacology, vol. 57, no. 3, pp. 642–649, 2000. View at Google Scholar · View at Scopus
  49. S. I. Chefer, E. D. London, A. O. Koren et al., “Graphical analysis of 2-[18F]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain,” Synapse, vol. 48, no. 1, pp. 25–34, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. A. S. Kimes, A. G. Horti, E. D. London et al., “2-[18F]F-A-85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans,” FASEB Journal, vol. 17, no. 10, pp. 1331–1333, 2003. View at Google Scholar · View at Scopus
  51. J. R. Ellis, V. L. Villemagne, P. J. Nathan et al., “Relationship between nicotinic receptors and cognitive function in early Alzheimer's disease: a 2-[18F]fluoro-A-85380 PET study,” Neurobiology of Learning and Memory, vol. 90, no. 2, pp. 404–412, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Fujita, M. Ichise, C. H. van Dyck et al., “Quantification of nicotinic acetylcholine receptors in human brain using [123I]5-I-A-85380 SPET,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 30, no. 12, pp. 1620–1629, 2003. View at Publisher · View at Google Scholar · View at Scopus
  53. E. M. Mitsis, K. P. Cosgrove, J. K. Staley et al., “Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT,” Neurobiology of Aging, vol. 30, no. 9, pp. 1490–1497, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. K. P. Cosgrove, J. Batis, F. Bois et al., “β2-nicotinic acetylcholine receptor availability during acute and prolonged abstinence from tobacco smoking,” Archives of General Psychiatry, vol. 66, no. 6, pp. 666–676, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. A. L. Brody, M. A. Mandelkern, M. R. Costello et al., “Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette,” International Journal of Neuropsychopharmacology, vol. 12, no. 3, pp. 305–316, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. O. Sabri, K. Kendziorra, H. Wolf, H. J. Gertz, and P. Brust, “Acetylcholine receptors in dementia and mild cognitive impairment,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 35, no. 1, pp. S30–S45, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. K. Kendziorra, H. Wolf, P. M. Meyer et al., “Decreased cerebral α4β2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography,” European Journal of Nuclear Medicine and Molecular Imaging. In press. View at Publisher · View at Google Scholar
  58. E. M. Mitsis, K. M. Reech, F. Bois et al., “123I-5-IA-85380 SPECT imaging of nicotinic receptors in Alzheimer disease and mild cognitive impairment,” Journal of Nuclear Medicine, vol. 50, no. 9, pp. 1455–1463, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. J. T. O'Brien, S. J. Colloby, S. Pakrasi et al., “α4β2 nicotinic receptor status in Alzheimer's disease using I-5IA-85380 single-photon-emission computed tomography,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 4, pp. 356–361, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. S. J. Colloby, E. K. Perry, S. Pakrasi et al., “Nicotinic 123I-5IA-85380 single photon emission computed tomography as a predictor of cognitive progression in alzheimer's disease and dementia with lewy Bodies,” American Journal of Geriatric Psychiatry, vol. 18, no. 1, pp. 86–90, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. J. R. Ellis, P. J. Nathan, V. L. Villemagne et al., “Galantamine-induced improvements in cognitive function are not related to alterations in α4β2 nicotinic receptors in early Alzheimer's disease as measured in vivo by 2-[18F]Fluoro-A- 85380 PET,” Psychopharmacology, vol. 202, no. 1–3, pp. 79–91, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. P. B. S. Clarke, “The fall and rise of neuronal α-bungarotoxin binding proteins,” Trends in Pharmacological Sciences, vol. 13, no. 11, pp. 407–413, 1992. View at Publisher · View at Google Scholar · View at Scopus
  63. H. Y. Wang, D. H. S. Lee, M. R. D'Andrea, P. A. Peterson, R. P. Shank, and A. B. Reitz, “β-Amyloid(1–42) binds to α7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology,” Journal of Biological Chemistry, vol. 275, no. 8, pp. 5626–5632, 2000. View at Publisher · View at Google Scholar · View at Scopus
  64. H. Y. Wang, D. H. S. Lee, C. B. Davis, and R. P. Shank, “Amyloid peptide Aβ(1–42) binds selectively and with picomolar affinity to α7 nicotinic acetylcholine receptors,” Journal of Neurochemistry, vol. 75, no. 3, pp. 1155–1161, 2000. View at Publisher · View at Google Scholar · View at Scopus
  65. M. R. D'Andrea, R. G. Nagele, H. Y. Wang, P. A. Peterson, and D. H. S. Lee, “Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease,” Histopathology, vol. 38, no. 2, pp. 120–134, 2001. View at Publisher · View at Google Scholar · View at Scopus
  66. G. Dziewczapolski, C. M. Glogowski, E. Masliah, and S. F. Heinemann, “Deletion of the α7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 29, no. 27, pp. 8805–8815, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. M. Bencherif and P. M. Lippiello, “α7 neuronal nicotinic receptors: the missing link to understanding Alzheimer's etiopathology?” Medical Hypotheses, vol. 74, no. 2, pp. 281–285, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. M. Bencherif, “Neuronal nicotinic receptors as novel targets for inflammation and neuroprotection: mechanistic considerations and clinical relevance,” Acta Pharmacologica Sinica, vol. 30, no. 6, pp. 702–714, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. D. Eddins, R. C. Klein, J. L. Yakel, and E. D. Levin, “Hippocampal infusions of apolipoprotein E peptides induce long-lasting cognitive impairment,” Brain Research Bulletin, vol. 79, no. 2, pp. 111–115, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. R. S. Bitner, A. L. Nikkel, S. Markosyan, S. Otte, P. Puttfarcken, and M. Gopalakrishnan, “Selective α7 nicotinic acetylcholine receptor activation regulates glycogen synthase kinase3β and decreases tau phosphorylation in vivo,” Brain Research, vol. 1265, no. C, pp. 65–74, 2009. View at Publisher · View at Google Scholar · View at Scopus
  71. G. G. Farías, A. S. Vallés, M. Colombres et al., “Wnt-7a induces presynaptic colocalization of α7-nicotinic acetylcholine receptors and adenomatous polyposis coli in hippocampal neurons,” Journal of Neuroscience, vol. 27, no. 20, pp. 5313–5325, 2007. View at Publisher · View at Google Scholar · View at Scopus
  72. S. Oddo, A. Caccamo, J. D. Shepherd et al., “Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction,” Neuron, vol. 39, no. 3, pp. 409–421, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. S. Oddo, A. Caccamo, K. N. Green et al., “Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 8, pp. 3046–3051, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. L. M. Billings, S. Oddo, K. N. Green, J. L. McGaugh, and F. M. LaFerla, “Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice,” Neuron, vol. 45, no. 5, pp. 675–688, 2005. View at Publisher · View at Google Scholar · View at Scopus
  75. A. Nordberg, E. Hellström-Lindahl, M. Lee et al., “Chronic nicotine treatment reduces β-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw),” Journal of Neurochemistry, vol. 81, no. 3, pp. 655–658, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. C. Unger, M. M. Svedberg, W. F. Yu, M. M. Hedberg, and A. Nordberg, “Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 317, no. 1, pp. 30–36, 2006. View at Publisher · View at Google Scholar · View at Scopus
  77. R. P. Brendza, B. J. Bacskai, J. R. Cirrito et al., “Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice,” Journal of Clinical Investigation, vol. 115, no. 2, pp. 428–433, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. A. Orr-Urtreger, F. M. Goldner, M. Saeki et al., “Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents,” Journal of Neuroscience, vol. 17, no. 23, pp. 9165–9171, 1997. View at Google Scholar · View at Scopus
  79. R. Paylor, M. Nguyen, J. N. Crawley, J. Patrick, A. Beaudet, and A. Orr-Urtreger, “α7 nicotinic receptor subunits are not necessary for hippocampal- dependent learning or sensorimotor gating: a behavioral characterization of Acra7-deficient mice,” Learning and Memory, vol. 5, no. 4-5, pp. 302–316, 1998. View at Google Scholar · View at Scopus
  80. E. Hoyle, R. F. Genn, C. Fernandes, and I. P. Stolerman, “Impaired performance of α7 nicotinic receptor knockout mice in the five-choice serial reaction time task,” Psychopharmacology, vol. 189, no. 2, pp. 211–223, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. J. W. Young, N. Crawford, J. S. Kelly et al., “Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice,” European Neuropsychopharmacology, vol. 17, no. 2, pp. 145–155, 2007. View at Publisher · View at Google Scholar · View at Scopus
  82. C. Fernandes, E. Hoyle, E. Dempster, L. C. Schalkwyk, and D. A. Collier, “Performance deficit of α7 nicotinic receptor knockout mice in a delayed matching-to-place task suggests a mild impairment of working/episodic-like memory,” Genes, Brain and Behavior, vol. 5, no. 6, pp. 433–440, 2006. View at Publisher · View at Google Scholar · View at Scopus
  83. J. J. Keller, A. B. Keller, B. J. Bowers, and J. M. Wehner, “Performance of α7 nicotinic receptor null mutants is impaired in appetitive learning measured in a signaled nose poke task,” Behavioural Brain Research, vol. 162, no. 1, pp. 143–152, 2005. View at Publisher · View at Google Scholar · View at Scopus
  84. C. M. Hernandez, R. Kayed, H. Zheng, J. D. Sweatt, and K. T. Dineley, “Loss of α7 nicotinic receptors enhances β-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 30, no. 7, pp. 2442–2453, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. K. Hashimoto, Y. Fujita, T. Ishima, H. Hagiwara, and M. Iyo, “Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: role of α7 nicotinic receptors,” European Journal of Pharmacology, vol. 553, no. 1–3, pp. 191–195, 2006. View at Publisher · View at Google Scholar · View at Scopus
  86. F. G. Boess, J. de Vry, C. Erb et al., “The novel α7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2- carboxamide improves working and recognition memory in rodents,” Journal of Pharmacology and Experimental Therapeutics, vol. 321, no. 2, pp. 716–725, 2007. View at Publisher · View at Google Scholar
  87. M. van Kampen, K. Selbach, R. Schneider, E. Schiegel, F. Boess, and R. Schreiber, “AR-R 17779 improves social recognition in rats by activation of nicotinic α7 receptors,” Psychopharmacology, vol. 172, no. 4, pp. 375–383, 2004. View at Publisher · View at Google Scholar · View at Scopus
  88. P. Pichat, O. E. Bergis, J. P. Terranova et al., “SSR180711, a novel selective α7 nicotinic receptor partial agonist: (II) efficacy in experimental models predictive of activity against cognitive symptoms of schizophrenia,” Neuropsychopharmacology, vol. 32, no. 1, pp. 17–34, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. K. Hashimoto, S. Nishiyama, H. Ohba et al., “[11C]CHIBA-1001 as a novel PET ligand for α7 nicotinic receptors in the brain: a PET study in conscious monkeys,” PLoS ONE, vol. 3, no. 9, article e3231, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. K. R. Tietje, D. J. Anderson, R. S. Bitner et al., “Preclinical characterization of A-582941: a novel α7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties,” CNS Neuroscience and Therapeutics, vol. 14, no. 1, pp. 65–82, 2008. View at Publisher · View at Google Scholar · View at Scopus
  91. R. Roncarati, C. Scali, T. A. Comery et al., “Procognitive and neuroprotective activity of a novel α7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders,” Journal of Pharmacology and Experimental Therapeutics, vol. 329, no. 2, pp. 459–468, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. C. A. Briggs, D. J. Anderson, J. D. Brioni et al., “Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo,” Pharmacology Biochemistry and Behavior, vol. 57, no. 1-2, pp. 231–241, 1997. View at Publisher · View at Google Scholar · View at Scopus
  93. J. J. Buccafusco, A. V. Terry Jr., M. W. Decker, and M. Gopalakrishnan, “Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys,” Biochemical Pharmacology, vol. 74, no. 8, pp. 1202–1211, 2007. View at Publisher · View at Google Scholar · View at Scopus
  94. Q. Liu, J. Zhang, H. Zhu, C. Qin, Q. Chen, and B. Zhao, “Dissecting the signaling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model,” FASEB Journal, vol. 21, no. 1, pp. 61–73, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. L. Chen, H. Wang, Z. Zhang et al., “DMXB (GTS-21) ameliorates the cognitive deficits in beta amyloid25-35-injected mice through preventing the dysfunction of α7 nicotinic receptor,” Journal of Neuroscience Research, vol. 88, no. 8, pp. 1784–1794, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. H. Y. Wang, K. Bakshi, C. Shen, M. Frankfurt, C. Trocmé-Thibierge, and P. Morain, “S 24795 limits β-amyloid-α7 nicotinic receptor interaction and reduces Alzheimer's disease-like pathologies,” Biological Psychiatry, vol. 67, no. 6, pp. 522–530, 2010. View at Publisher · View at Google Scholar · View at Scopus
  97. K. Hashimoto and M. Iyo, “Amyloid cascade hypothesis of Alzheimer's disease and α7 nicotinic receptor,” Nihon Shinkei Seishin Yakurigaku Zasshi, vol. 22, no. 2, pp. 9–53, 2002. View at Google Scholar
  98. J. Toyohara and K. Hashimoto, “α7 nicotinic receptor agonists: potential therapeutic drugs for treatment of cognitive impairments in schizophrenia and Alzheimer's disease,” Open Medicinal Chemistry Journal, vol. 4, pp. 37–56, 2010. View at Google Scholar
  99. A. Nordberg, “Human nicotinic receptors—their role in aging and dementia,” Neurochemistry International, vol. 25, no. 1, pp. 93–97, 1994. View at Publisher · View at Google Scholar · View at Scopus
  100. A. Nordberg, “Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications,” Biological Psychiatry, vol. 49, no. 3, pp. 200–210, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. P. J. Whitehouse and R. N. Kalaria, “Nicotinic receptors and neurodegenerative dementing diseases: basic research and clinical implications,” Alzheimer Disease and Associated Disorders, vol. 9, supplement 2, pp. 3–5, 1995. View at Google Scholar
  102. C. M. Martin-Ruiz, J. A. Court, E. Molnar et al., “α4 but not α3 and α7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer's disease,” Journal of Neurochemistry, vol. 73, no. 4, pp. 1635–1640, 1999. View at Publisher · View at Google Scholar · View at Scopus
  103. P. Davies and S. Feisullin, “Postmortem stability of α-bungarotoxin binding sites in mouse and human brain,” Brain Research, vol. 216, no. 2, pp. 449–454, 1981. View at Publisher · View at Google Scholar · View at Scopus
  104. E. Engidawork, T. Gulesserian, N. Balic, N. Cairns, and G. Lubec, “Changes in nicotinic acetylcholine receptor subunits expression in brain of patients with Down syndrome and Alzheimer's disease,” Journal of Neural Transmission, Supplement, no. 61, pp. 211–222, 2001. View at Google Scholar
  105. L. Falk, A. Nordberg, A. Seiger, A. Kjaeldgaard, and E. Hellström-Lindahl, “Higher expression of α7 nicotinic acetylcholine receptors in human fetal compared to adult brain,” Developmental Brain Research, vol. 142, no. 2, pp. 151–160, 2003. View at Publisher · View at Google Scholar · View at Scopus
  106. A. Marutle, X. Zhang, J. Court et al., “Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia,” Journal of Chemical Neuroanatomy, vol. 22, no. 1-2, pp. 115–126, 2001. View at Publisher · View at Google Scholar · View at Scopus
  107. J. A. Court, E. K. Perry, D. Spurden et al., “The role of the cholinergic system in the development of the human cerebellum,” Developmental Brain Research, vol. 90, no. 1-2, pp. 159–167, 1995. View at Publisher · View at Google Scholar
  108. J. Court, C. Martin-Ruiz, M. Piggott, D. Spurden, M. Griffiths, and E. Perry, “Nicotinic receptor abnormalities in Alzheimer's disease,” Biological Psychiatry, vol. 49, no. 3, pp. 175–184, 2001. View at Publisher · View at Google Scholar · View at Scopus
  109. R. W. James, N. A. Bersinger, B. Schwendimann, and B. W. Fulpius, “Characterization of iodinated derivatives of α-bungarotoxin,” Hoppe-Seyler's Zeitschrift fur Physiologische Chemie, vol. 361, no. 10, pp. 1517–1524, 1980. View at Google Scholar · View at Scopus
  110. A. R. L. Davies, D. J. Hardick, I. S. Blagbrough, B. V. L. Potter, A. J. Wolstenholme, and S. Wonnacott, “Characterisation of the binding of [3H]methyllycaconitine: a new radioligand for labelling α7-type neuronal nicotinic acetylcholine receptors,” Neuropharmacology, vol. 38, no. 5, pp. 679–690, 1999. View at Publisher · View at Google Scholar · View at Scopus
  111. H. A. Navarro, D. Zhong, P. Abraham, H. Xu, and F. I. Carroll, “Synthesis and pharmacological characterization of [125I]iodomethyllycaconitine ([125I]iodo-MLA). A new ligand for the α(7) nicotinic acetylcholine receptor,” Journal of Medicinal Chemistry, vol. 43, no. 2, pp. 142–145, 2000. View at Publisher · View at Google Scholar · View at Scopus
  112. J. Toyohara, J. Wu, and K. Hashimoto, “Recent development of radioligands for imaging α7 nicotinic acetylcholine receptors in the brain,” Current Topics in Medicinal Chemistry, vol. 10, no. 15, pp. 1544–1557, 2010. View at Google Scholar
  113. Y. Tanibuchi, J. Wu, J. Toyohara, Y. Fujita, M. Iyo, and K. Hashimoto, “Characterization of [3H]CHIBA-1001 binding to α7 nicotinic acetylcholine receptors in the brain from rat, monkey, and human,” Brain Research, vol. 1348, no. C, pp. 200–208, 2010. View at Publisher · View at Google Scholar
  114. J. Toyohara, M. Sakata, J. Wu et al., “Preclinical and the first clinical studies on [11C]CHIBA-1001 for mapping α7 nicotinic receptors by positron emission tomography,” Annals of Nuclear Medicine, vol. 23, no. 3, pp. 301–309, 2009. View at Publisher · View at Google Scholar · View at Scopus
  115. M. Sakata, J. Wu, J. Toyohara et al., “Biodistribution and radiation dosimetry of the α7 nicotinic acetylcholine receptor ligand [11C]CHIBA-1001 in humans,” Nuclear Medicine and Biology. In press. View at Publisher · View at Google Scholar
  116. J. Wu, J. Toyohara, Y. Tanibuchi et al., “Pharmacological characterization of [125I]CHIBA-1006 binding, a new radioligand for α7 nicotinic acetylcholine receptors, to rat brain membranes,” Brain Research, vol. 1360, no. C, pp. 130–137, 2010. View at Publisher · View at Google Scholar