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

Disease: Therapeutic Implications

Agneta Nordberg

The neuronal nicotinic acetylcholine receptors (nAChRs) in the brain are important for functional processes, including cognitive and memory functions. The nAChRs acting as neuromodulators in communicative processes regulated by different neurotransmitters show a relatively high abundance in the human cortex, with a laminar distribution of the nAChRs of superhigh, high, and low affinity in the human cortex. The regional pattern of messenger RNA (mRNA) for various nAChR subtypes does not strictly follow the regional distribution of nAChR ligand-binding sites in the human brain. Consistent losses of nAChRs have been measured in vitro in autopsy brain tissue of Alzheimer’s disease patients (AD), as well as in vivo by positron emission tomography (PET). Measure-ment of the protein content of nAChRs showed reduced levels of thea4,a3, anda7 nAChR subtypes. The finding that thea4 anda3 mRNA levels were not changed in AD brains suggests that the losses in high-affinity nicotinic-binding sites cannot be attributed to alterations at the transcriptional level of thea4 anda3 genes and that the causes have to be searched for at the translational and/or posttranslational level. The increased mRNA level of the a7 nAChR subtyep in the hippocampus indicates that subunit-specific changes in gene expression of the a7 nAChR might be associated with AD. The PET studies reveal deficits in nAChRs as an early phenomena in AD, stressing the importance of nAChRs as a potential target for drug intervention. PET ligands measuring the a4 nAChRs are under development. Studies of the influence of b-amyloid on nAChRs in brain autopsy tissue from pa-tients with the amyloid precursor protein 670/671 muta-tion have shown that there is no direct relamuta-tionship between nAChR deficits and pathology. Treatment with cholinergic drugs in AD patients indicate improvement of the nAChRs in the brain, as visualized by PET. Further studies on neuroprotective mechanisms mediated via nAChR subtypes are exciting new avenues. Biol Psychi-atry 2001;49:200 –210 © 2001 Society of Biological Psychiatry

Key Words: AD, human brain, nicotinic receptor sub-types, PET ligands, nicotinic agonists, APP 670/671, cholinesterase inhibitors

Introduction

T

he neuronal nicotinic acetylcholine receptors (nAChRs) are transmitter-gated ion channels that belong to a superfamily of ion channels of homologous receptors including g-aminobutyric acid, glycine, and serotonin 3 (5-HT3) (Karlin and Akabas 1995; Paterson

and Nordberg 2000; Sargent 1993, 2000). The nAChRs are obvious candidates for transducing cell surface inter-actions, not only for acetylcholine but also for other neurotransmitters (Kaiser et al 2000; Wonnacott 1997). Experimental data suggest that the nAChRs might act as neuromodulators in communicative processes in the brain (Kaiser et al 2000; Lindstro¨m 1997; Wonnacott 1997). It is therefore of great importance to define by which mecha-nisms the nAChRs exert their action in the brain. The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000). The exact role of nAChRs and their full potential as a therapeutic target in these diseases have yet to be clarified. Interestingly enough, a considerable body of evidence exists to suggest that the nAChRs are involved in cognitive and memory functions (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Sahakian and Coull 1994).

Alzheimer’s disease is the most common form of dementia and one of the most devastating diseases of the middle aged and elderly. Although the last decade has witnessed a steadily increasing effort directed at discovery of the etiology and neuropathologic and neurochemical mechanisms involved in the disease, there is still no cure (Braak and Braak 1998; Cohen-Mansfield 2000; Fratigli-oni et al 1999; Hardy 1997; Master and Beyreuther 1998; St George-Hyslop 2000,). However, extensive research activities have stimulated the development of new

From the Department of NEUROTEC, Division of Molecular Neuropharmacology, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden. Address reprint requests to Agneta Nordberg, M.D., Ph.D., Department of

NEU-ROTEC, Division of Molecular Neuropharmacology, Huddinge Hospital B84, S-141 86 Huddinge, Sweden.

Received June 1, 2000; revised November 13, 2000; accepted December 8, 2000.

© 2001 Society of Biological Psychiatry 0006-3223/01/$20.00

treatment strategies in AD, and several drugs that improve cholinergic transmitter activity have reached clinical use (for a review, see Nordberg and Svensson 1998). The role of nAChRs in AD is discussed below, with the focus mainly on new therapeutic implications.

nAChRs in the Human Cortex

The nAChRs are distributed in many regions of the human brain. So far the nAChR subunitsa3,a4,a5,a7,b2,b3, and b4 have been cloned (Anand and Lindstrom 1990; Chini et al 1994; Fornasari et al 1990; Matter and Ballivet 2000; Raimondi et al 1991; Willoughby et al 1993). The distribution of the nAChRs and their transcripts have been mapped in vitro in the human brain, using autoradiography (Adem et al 1988, 1989; Court and Perry 1994; Sihver et al 1998b), in situ hybridization (Rubboli et al 1994; Wever et al 1994), and reverse transcription polymerase chain reaction (Hellstro¨m-Lindahl et al 1998). In vitro receptor binding studies in human autopsy brain tissue suggest that nAChRs are heterogeneous and can be rationalized to three different nAChR sites (superhigh, high, and low affinity) (Marutle et al 1998; Nordberg et al 1988; Warp-man and Nordberg 1995). The distribution of high-affinity nAChRs was studied with [3H]nicotine and [3 H]epibati-dine as radioactive receptor ligands (Marutle et al 1998; Sihver et al 1998b). Two high-affinity nAChR sites were identified in the human cortex with [3H]epibatidine, most likely representing the a3 and a4b2 nAChR subtypes. Differences in the regional binding between [3H]nicotine and [3H]epibatidine were observed in the human brain, with a proportionally higher level of [3H]epibatidine binding sites in the thalamus and cerebellum. The differ-ence possibly reflects a selectivity for different nAChR subtypes between the nAChR ligands, nicotine, and epi-batidine—that is, a greater selectivity for [3H]epibatidine for the a3 nAChRs in the human brain (Marutle et al 1998).

The laminar distribution of nAChRs in human cortex was studied in autopsy brain tissue, using autoradiographi-cal analysis and the nAChR ligands [3H]nicotine, [3 H]epi-batidine, and [3H]cytisine (Sihver et al 1998b). A general high binding was observed in layers 1, 11, and V, with particularly high levels in the layer of primary sensory motor cortex and the inferior frontal sulcus (Sihver et al 1998b). All three ligands appeared to bind to a common high-affinity binding site, which most likely represents binding to the nAChRa4 subunits. A significantly greater binding for [3H]nicotine and [3H]epibatidine than for [3H]cytisine is observed in areas of the primary motor cortex, layer 111b of the occipital cortex, and layer V of the superior temporal sulcus, most likely representing binding of an additional nAChR site. High levels of

[3H]nicotine binding have been observed in layers 1 and V1 of the primary cortex, deeper layer V of the primary cortex, layer 111 of the superior temporal sulcus, and layer V1 of the parietal cortex. This suggests the presence of an additional third nAChR site in the human cortex (Sihver et al 1998b) that may be the a7 nAChR subtype.

The distribution of messenger RNA (mRNA) for differ-ent nAChR subunits has been examined in differdiffer-ent cortical layers (Schro¨der et al 1995). Thea4 mRNA seems to be abundant in all layers except 1 and IV of the frontal cortex (Schro¨der et al 1995). The a3 mRNA has been found to be most prominently expressed in the pyramidal neuron layers 111–V1, moderately expressed in layer 11, and minimally expressed in layer IV of the human cortex (Schro¨der et al 1995; Wever et al 1994). A high expression ofa7 mRNA was observed in layers 11 and 111, moderate in layers V and V1, and low in layers I and IV of the human cortex (Schro¨der et al 1995). A significant decrease in [3H]epibatidine binding has been observed with aging in the human cortical brain regions and cerebellum (Ma-rutle et al 1998). The levels ofa4 anda7 nAChR mRNA showed a decrease with aging, whereas the levels ofa3 mRNA were unchanged in the elderly brain relative to the fetal brain (Hellstro¨m-Lindahl et al 1998). Interestingly, the observed regional pattern of expression of nAChR subunit mRNA in the human brain does not directly correspond to the regional pattern of nAChR binding sites revealed by ligand-binding studies.

nAChR Changes in AD

A consistent, significant loss of nAChRs has been ob-served in cortical autopsy brain tissue from AD patients relative to age-matched healthy subjects (Nordberg and Winblad 1986). More recently, we have have found that the nAChR deficits in AD brains probably represent an early phenomenon in the course of the disease, which can be detected in vivo by positron emission tomography (PET) (Nordberg et al 1990, 1995, 1997). The cortical nAChR deficits significantly correlate with cognitive im-pairment in AD patients (Nordberg, in press; Nordberg et al 1995, 1997).

the vesamicol binding sites may be more preserved in the existing presynaptic terminals of AD cortical tissue, thereby expressing a compensatory capacity to maintain cholinergic activity. In addition, the observation suggests that nAChRs are present on noncholinergic nerve termi-nals to a significant extent. Basal forebrain lesions in rats, with the selective cholinergic immunotoxin 192Ig saporin and ibotenic acid, also show the rich presence of nAChRs on noncholinergic nerve terminals (Bednar et al 1998), supporting the assumption of nAChR as a neuromodulator also in noncholinergic nerve terminals (Kaiser et al 2000). b-Amyloid (Ab) is also an important factor, which may initiate and promote AD (Selkoe 1999). Recently, the possible role of Ab as a neuromodulator in the brain has stressed the possible regulatory mechanisms between Ab and cholinergic neurotransmission and nAChRs in the

was approximately 15 years younger than the sporadic patients. Both positive and negative correlations were observed between the number of nAChR binding sites and the number of neuronal plaques and neurofibrillary tan-gles, respectively, in the temporal cortex and parietal cortex of mutation carriers. This finding suggests that these processes may be closely related but not directly dependent on each other (Figure 2). Different brain re-gions may show different kinetics for the development of neurofibrillary tangles and neuritic plaques. We have recently characterized the nAChRs in APP 670/671 trans-genic mice and found compensatory mechanisms for some of the nAChR subtypes, which correlates to behavior and pathology in the transgenic mice (Paterson et al, unpub-lished data).

A decrease in the protein levels of the a3 and a4 nAChR subunits was recently measured in the temporal cortex and of thea3,a4, anda7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b). A decrease in protein levels of

the a4 nAChR but not of the a3 and a7 nAChRs was reported by Martin-Ruiz et al (1999). The explanation for the differences in results obtained by Martin-Ruiz et al (1999) and Guan et al (2000b) is unknown. Lee et al (2000) recently also reported a significant decrease in the a7 nAChR protein level of the AD hippocampus. Inter-estingly, a reduction in the protein level ofa7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the a4 nAChR protein level (Guan et al 1999). The deficits in nAChRs seen in AD brains may be related to alterations of the nAChR synthesis on different levels such as transcription, translation and postranslation modifications, and receptor turnover.

Examination of the regional expression of mRNA of the nAChRa4 and a3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hell-stro¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the a7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999). The studies suggest that the nAChR deficits in AD brains mainly reflect posttranscriptional events (Hellstro¨m-Lindahl et al 1999; Schro¨der and Wever 1998). The mechanisms for changes in protein levels of nAChRs in AD are unclear. Possible factors such as amyloid peptide accumulation, hyperphosphorylation of tau protein, oxidative stress, and modification of cell membrane during the development of AD may be related to decreased protein levels of nAChRs (Farooqui et al 1995; Smith et al 1996). Interestingly enough, lipid peroxidation has been shown to decrease the number of nAChRs in PC12 cells (Guan et al 2000a).

Visualization of nAChRs in AD by PET

Significant progress has been made during recent years in developing and applying functional brain imaging tech-niques to allow for early diagnosis of AD and evaluation of drug treatment efficacy. Positron emission tomography might be a suitable method for functional studies of pathologic changes in the brain, not only revealing dys-functional changes early in the course of the disease but also providing a deep insight into the functional mecha-nisms of new potential drug treatment strategies. A limited number of PET ligands are so far available for mapping the cholinergic system in the human brain (Table 1).

[11C]Physostigmine, [11C]MPA4A, and [11C]PMP have been used in PET studies to measure acetylcholinesterase in brains of healthy volunteers (Kuhl et al 1999; Namba et al 1999; Pappata et al 1996). Positron emission tomogra-phy studies have revealed a reduced cortical acetylcho-linesteserase activity in AD patients (Iyo et al 1997; Kuhl et al 1999). A progressive loss of cortical acetylcholines-terase activity has been observed in AD patients with Figure 2. (A) Correlation between neuronal plaques and [3

H]nic-otine binding in the temporal cortex and parietal cortex of four patients (P1–P4) carrying the Swedish amyloid precursor protein (APP) 670/671 mutation. (B) Correlation between neurofibrillary tangles and [3

cognitive decline (Shinotoh et al 2000). The presynaptic vesicular acetylcholine transporter vesamicol ([123 I]iodo-benzovesamicol) has been used in vivo as a marker of presynaptic cholinergic activity in single photon emission computed tomography (SPECT) studies (Kuhl et al 1996). Greater reduction in [123I]iodobenzovesamicol binding was observed throughout the cerebral cortex in AD pa-tients with early onset of the disease (Kuhl et al 1996). The loss in cortical acetylcholinesterase activity was less pro-nounced in mildly demented AD patients relative to autopsy material and did not strictly correlate with cere-bral glucose metabolism impairment (Kuhl et al 1999).

The development of methods for the synthesis of radiolabeled nicotinic ligands with short half-life [11C] has enabled the study of the binding of [11C]nicotine in both normal and AD brains by PET (Nordberg et al 1990, 1995). The use of [11C]nicotine in PET studies was reviewed by Mazie´re and Delforge (1995), who identified some problems with the tracer due to high nonspecific binding, rapid metabolism, and rapid washout from the brain. [11C]Nicotine has drawbacks such as rapid dissoci-ation from the receptor ligand and strong dependence of accumulation on cerebral blood flow. Different kinetic modeling approaches have been developed to improve the analysis of the PET studies, and the dual tracer kinetic rate constant (k2*) model for [

11

C]nicotine compensates for some of the problems (Lundqvist et al 1998). The mea-surement of [11C]nicotine in the human brain in vivo by PET (k2*) agrees with the distribution of nAChRs

ob-served by in vitro radioligand binding in human brain tissue autopsy (Nordberg 2000b). A significant decrease in [11C]nicotine binding (increase in k2* value) was

mea-sured in the temporal cortex, frontal cortex, and hippocam-pus (Nordberg et al 1995, 1997). Selective cortical deficits in [11C]nicotine binding are often observed by PET early in the course of the AD disease (Figure 3A). A significant correlation can be observed between cognitive function and nicotinic receptor binding (k2*) (Figure 3A). The

findings might be promising in that PET imaging com-bined with genetic testing (e.g., apolipoprotein E typing) could be used to detect subjects with a greater risk of developing AD.

The past several years have seen an expanded effort to develop PET probes for noninvasive study of nAChRs. This has also led to the search for new nAChR PET ligands. A ligand with a selectivity for thea4b2 nAChRs would be particularly preferable because the a4b2 has been recognized as the predominant subtype that is defi-cient in AD (for a review, see Sihver et al 2000). Several PET ligands have been synthesized, including [11 C]ABT-418, [11C]MPA, and [76Br]BAP (A-85380) (Sihver et al 1998a, 1999a, 1999b) (Figure 4). [11C]MPA and [76Br]BAP (A-85380) showed a more distinct binding pattern in the rat brain relative to [11C]nicotine and [11C]ABT, as revealed by autoradiography (Figure 3B). Administration of the PET ligands to monkeys also re-vealed a slower binding dissociation, and higher specific binding for [11C]MPA and [76Br]A-85380 than for [11C]nicotine and [11C]nicotine (Sihver et al 1999a, 1999b). The very high affinity for [76Br]A-85380, the high specific in vivo uptake seen in monkeys (Figure 3C), and thereby the possible a4b2 nAChR selectivity increase interest in using the ligand in human PET studies. The application of A-85830 analog with an [11C] label is ongoing. Positron emission tomography studies using 2-[18F]A-85380 and SPECT studies with [123I]5-A-85380 have recently been performed in monkeys (Fujita et al 2000; Sihver et al 2000). Both PET and SPECT studies reveal a high uptake of the radioligand to areas rich in a2b2 nAChR such as the thalamus (Figure 3C). Recently, several epibatidine analogs such as norchloro[18F]fluoroepibatidine (Ding et al 2000) have been developed, but it is still uncertain whether the epibatidine analogs can be applied in humans due to risk of toxicity.

Positron emission tomography studies not only allow

Table 1. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) Ligands for Visualization of Cholinergic Activity in the Human Brain

Parameter Radioligand

Imaging

technique References Acetylcholinesterase [11_{C]MP4A PET Iyo et al 1997}

[11_{C]PMP PET Kuhl et al 1999}

Cholinergic terminals [123_{I]IBVM SPECT Kuhl et al 1996}

Nicotinic receptors [11_{C]Nicotine PET Nordberg et al 1990, 1995}

Nyba¨ck et al 1994 Muzic et al 1998 Muscarinic receptors [11_{C]Benztropine PET Dewey et al 1990}

[11_{C]QNB SPECT Weinberger et al 1991}

measurement of nAChRs in steady-state situation in AD, but also allow measurement of nAChRs during functional activation studies. We have recently performed studies

where functional activation patterns in the brain during an episodic memory task in healthy subjects as well as in AD patients have been measured by cerebral blood flow

Figure 3. (A) (Top) Horizontal positron emission tomography images of the uptake and distribution of [11

C]nicotine at the level of the basal ganglia (left) and the frontal association cortex–parietal cortex (right) in the brain of an Alzheimer’s disease patient with mild dementia. The figure represents a summation picture of the brain uptake of [11

C] radioactivity after an intravenous injection of a tracer dose of [11

C]nicotine. The color scale indicates radioactivity expressed in nCi/cm3

/body weight. Red, high uptake; yellow, medium uptake; green, low uptake. The patient shows left-side cortical deficits in [11

C]nicotine. (Bottom) Correlation between cognitive function (Mini-Mental State Examination [MMSE] score) and nicotinic receptor binding (k2* rate constant) in the temporal cortex of Alzheimer’s patients. p,.001. (B) Binding of

different nicotinic acetylcholine receptor ligands in the rat brain as visualized by in vitro autoradiography of coronal (left) and sagittal (middle) rat brain sections. (Right) The nonspecific binding obtained in the presence of 100mmol/L (2)nicotine is shown in the sagittal sections. The binding density increases in the sequence black, yellow, red, white. ctx, cortex; hip, hippocampus; th, thalamus; cbl, cerebellum; str, striatum; MPA, (R,S)-1-methyl-2-(3-pyridyl)azetidine; BAP, bromo-3-[[2(5)-azetidinyl]methoxy] pyridine. Data are from Sihver et al (1998a, 1999a).

(C) (a) Positron emission tomography image of [76

Br]Br-A-85380 in a rhesus monkey brain (transverse section). The total uptake was determined at a baseline scan (left), and a second scan was performed 3.5 hours later after injection of 0.5 mg/kg cytisine to block the uptake of [76

Br]Br-A-85380 (right). The ratios of total to block were 2.5 in the thalamus and 1.2 in the cortex. (b) Distribution of [76

changes with PET (Ba¨ckman et al 1997, 1999). In some ongoing studies we are now measuring the changes in nAChRs in different brain regions before and during task performances such as attentional tests. This type of study will provide further insight into the regional network in the brain, where nAChRs play an important role, and how drug treatment can improve brain function.

nAChRs: Target for AD Treatment?

Transmitter replacement therapy is the mainstay treatment for AD. Cholinergic therapy is based on the assumption that low levels of acetylcholine are responsible for the cognitive decline associated with AD. Cholinesterase in-hibitors including tacrine, donepezil, rivastigmine, and galantamine have in clinical studies shown palliative effects on symptoms and some trend to slow disease progression (Giacobini 2000; Nordberg and Svensson 1998; Van den Berg et al 2000). It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000).

Positron emission tomography and SPECT studies per-formed in AD patients under treatment with cholinergic drug therapy have shown an improvement in the cerebral blood flow and glucose metabolism (Nordberg 1999). In addition, PET studies also have revealed an improvement in nAChRs in AD patients during long-term treatment with cholinesterase inhibitors such as tacrine and NXX-066 (Nordberg 2000; Nordberg et al 1992, 1998). Since an

enhanced activity of acetylcholinesterase has been mea-sured in cerebrospinal fluid following long-term treatment with tacrine (Nordberg et al 1999), possibly as a result of an increased acetylcholinesterase gene expression, it might be an advantage to use drugs interacting with nAChRs. Nerve growth factor intraventricularly administered to AD patients for 3 months resulted in an increased [11 C]nico-tine binding (Eriksdotter-Jo¨nhagen et al 1998), whereas treatment with the 5-HT3blocker ondansetron showed a

cholinesterase inhibitors produce similar improvement in cognitive function in AD patients (Nordberg et al 1998). Although epidemiologic data are somewhat conflicting about the possibility that smoking can protect against AD (Doll et al 2000; Van Duijn et al 1995), experimental data suggest that a neuroprotective effect against Ab toxicity might be obtained via the nAChR (e.g., the a7 subtype) (Kihara et al 1997; Svensson and Nordberg 1998; Zamani et al 1997). Estrogen, which in epidemiologic studies has been shown to reduce the risk of AD (Henderson 1997), has in experimental studies in PC 12 cells shown neuro-protective effects against Ab toxicity that are at least partly mediated by thea7 subtype nAChR (Svensson and Nordberg 1998). It is reasonable to assume that to obtain significant neuroprotective effects the drug probably must be given during a very early stage of AD, probably a presymptomatic level. There are tremendous possibilities for the development of nAChR agonists as potential therapeutic agents in AD.

This study was supported by grants from the Swedish Medical Research Council (Project No. 05817), Loo and Hans Osterman’s foundation, Stohne’s foundation, the Swedish Alzheimer foundation, Foundation for Old Servants, and Swedish Match.

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 supported by the Society of Biological Psychiatry through an unrestricted educational grant provided by Janssen Pharmaceutica LP.

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