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Alzheimer's disease and acetylcholine

Takeshi Kihara and Shun Shimohama
Department of Neurology, Graduate School of Medicine, Kyoto University,54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan Abstract. Cholinergic abnormalities, alongside senile plaques, neurofibrillary
tangles, and extensive neuronal loss, are the major characteristics in
Alzheimer's disease (AD). Both nicotinic and muscarinic acetylcholine
receptors are decreased in AD, and it has been shown that the reduction in thenumber of acetylcholine receptors precedes other pathologic changes.
Anti-cholinergic drugs induce amnesia, which can be reversed by withdrawalof the medication. Inhibition of the down-regulation of acetylcholine is,therefore, a strategy for the treatment of AD because it could augmentacetylcholine levels within synaptic clefts. In this context,acetylcholinesterase inhibitors, which improve cognitive functions, arecurrently approved for the treatment of AD. Stimulation of acetylcholinereceptors, nicotinic or muscarinic, is another strategy; some drugs arecurrently under investigation, and reported to be effective. In addition,nicotinic stimulation exerts a neuroprotective effect, and reduces the amyloidburden. Cholinergic therapy may counter the symptoms and progress of AD.
The correspondence should beaddressed to S. Shimohama, Email: Key words: Alzheimer's disease, amyloid-b, nicotinic acetylcholine receptor,
a4b2, a7, muscarinic acetylcholine receptor INTRODUCTION
Epidemiological studies have suggested that smok- ing is associated with a lower incidence of AD (Hillier Alzheimer's disease (AD) is one of the neurodegener- and Salib 1997, Lee 1994, van Duijn and Hofman ative diseases presenting with dementia, and there are 1991), and an inverse association between smoking and no definitive treatments or prophylactic agents. The Alzheimer's disease has been suggested by some stud- presence of two types of abnormal deposits, senile ies. Nicotinic cholinergic stimulation might counter or plaques and neurofibrillary tangles, and extensive delay the development of AD. However, these ideas are neuronal loss characterize the pathology of AD.
Cholinergic abnormalities have been observed in AD In this review, the association of cholinergic abnor- brains (Shimohama et al. 1986, Whitehouse et al. 1986).
malities and AD, and implications for the treatment of It has been reported that the protein level of acetylcho- line receptors is reduced in AD (Nordberg 2001), andthat dysfunction of cholinergic signal transmission EPIDEMIOLOGICAL DATA OF AD
could be responsible for the symptoms of AD. In addi-tion, anti-cholinergic drugs, used for the treatment of It is well known that aging is the most important risk Parkinson's disease, induce amnesia, which clinically factor for dementia including AD. The prevalence and resembles the symptoms of AD (Bymaster et al. 1993).
incidence of dementia doubles every 5 years in persons The amnesia induced by anti-cholinergic drugs can be reversed by withdrawal of the drugs. This phenomenon A family history of dementia in first-degree relatives implies that augmentation of the concentration of ace- has been shown to increase the risk of developing de- tylcholine within the surviving synaptic clefts could mentia. Genetic abnormalities have been found in some families with autosomal dominant inheritance of AD.
Anti-cholinergic drug-induced amnesia is thought to be Amyloid-b protein precursor (AbPP), presenilin 1 and due to the blockade of muscarinic acetylcholine recep- 2, have been associated with early onset of autosomal tors since it has also been reported that muscarinic dominant inherited AD. It has been shown that these ge- agonists improve memory (Terry Jr. et al. 2002).
netic abnormalities lead to the over-production of amy- Conversely, it has been shown that smoking im- loid-b, which is the major protein component of senile proves arousal and attention, and memory. Nicotinic acetylcholine receptor stimulation might enhance the It is controversial whether smoking is associated with formation of memory (Potter et al. 1999) alongside its the incidence of AD. Some reports have indicated the protective effect against the development of AD (Kihara negative relationship between smoking and AD (Hillier et al. 1997, 1998, 2001, Shimohama et al. 1996). Sub- and Salib 1997, Lee 1994, van Duijn and Hofman cutaneous administration of nicotine significantly im- 1991). Van Duijn and Hofman (1991) reported that the risk of Alzheimer's disease decreased with the increase Conners’ continuous performance test (CPT) (White in the daily number of cigarettes smoked before onset of and Levin 1999). It has been reported that a significant disease (relative risk 0.3 in those smoking greater than reduction in errors of omission in the CPT occurred 21/day vs. 1 in non-smokers). They concluded that there throughout the period of chronic nicotine administra- is an inverse association between smoking and AD, al- tion. No improvement in motor or memory function though smoking cannot be advocated for other health was observed. Nicotine is known to act on presynaptic reasons. Hebert et al. (1992) suggested that smoking nicotinic acetylcholine receptors (nAChR) to enhance does not increase the risk of AD. Lee (1994) reviewed glutamatergic transmission. Nicotine from tobacco is 19 case-control studies on the association between AD thought to influence cognition by enhancing synaptic and smoking, and showed a highly significant transmission. Conversely, decreased efficacy in trans- (P<0.001) negative association (ever/never smokers, mission may account for the deficits associated with the relative risk (RR) 0.64, 95% confidence interval (CI) loss of cholinergic innervation during AD. It is clear that 0.54-0.76). This negative or inverse association smoking cannot be advocated for a variety of health rea- suggests that nicotine protects against AD.
sons, but these data imply that nicotine could protect Letenneur et al. (1994) showed, however, that al- though current smokers and past smokers had a lower AD and ACh receptors 101
risk of cognitive deficit than non-smokers, this signifi- fusiform and bulbous, are surrounded by reactive glial cant relationship disappeared after adjustment for po- tential confounding factors such as occupational A reduction in the number of nAChR in the cerebral category. They suggested that the apparent protective cortex of AD patients has been detected using ligand effect of smoking habits on cognitive abilities could be due to a confounding effect of occupational category.
Shimohama et al. (1986) showed that, not only nicotinic Launer et al. (1999) reported that smoking did not pro- receptors, but also muscarinic acetylcholine receptors tect against AD, contrary to previous reports. Wang et are decreased in AD brains. The number of [ H]nicotine al. (1999) also observed that smoking does not seem binding sites in the AD brain was significantly reduced protective against AD or dementia. Other reports have in the putamen and the nucleus basalis of Meynert.
suggested that smoking is one of the risk factors of AD [ H]QNB binding was significantly reduced in the hip- (Doll et al. 2000, Meyer et al. 1999). Almeida et al.
pocampus and nucleus basalis of Meynert. These find- (2002) recently reviewed case-control and cohort stud- ings suggest that there are significant changes in the ies, and concluded that the nature of the association be- level of both nicotinic and muscarinic cholinergic re- tween smoking and AD remains unclear. Overall, ceptors in selected regions of AD brains. Perry et al.
epidemiological data on the association between nico- (1995) examined high-affinity nicotine binding, consid- tinic acetylcholine dysfunction and AD is unclear, and ered to primarily reflect the presence of CNS much more information is required to establish the facts.
Muscarinic cholinergic abnormalities are also sus- autoradiographically in the brain regions most severely pected in AD brains. The cholinergic antagonist, sco- affected by AD pathology. Abnormalities in the nico- polamine, leads to memory impairment in humans tinic receptor were closely associated with primary (Drachman and Leavitt 1974, Ghoneim and Mewaldt 1977). It was reported that learning and acquisition of neurofibrillary tangles in subicular and entorhinal areas new information were impaired, and this phenomenon in AD brains. Therefore, it is notable that abnormalities is similar to the early amnesic symptoms of AD. An- in nicotinic receptors, especially alpha4beta2 (a4b2) other cholinergic antagonist, trihexyphenidyl, is pre- nAChR, occur in the early stages of the pathological scribed for the treatment of Parkinson's disease, and this process, not only in AD but also in other neurodegenera- drug sometimes induces amnesia in these patients.
tive diseases. It is possible that nicotinic receptor These findings suggest that both nicotinic and down-regulation precedes neurodegeneration and the muscarinic acetylcholine receptors may be involved in difference between the diseases might depend upon the AD pathogenesis, although the precise mechanism re- distribution of the abnormal nicotinic receptors.
Nordberg (2001) showed that the protein content of alpha4 (a4), alpha3 (a3), and alpha7 (a7) nAChR is re- PATHOLOGY ASSOCIATED WITH
duced in AD brains. The regional pattern of messenger ACETYLCHOLINE RECEPTORS
RNA (mRNA) for nAChR does not strictly follow theregional distribution of nAChR ligand-binding sites in The presence of two deposits, senile plaques (SPs) and the human brain. Alpha4 and alpha3 mRNA levels were neurofibrillary tangles (NFTs), and extensive neuronal not changed in AD brains and the mRNA level of the death characterize the pathology of AD. Cholinergic ab- alpha7 nAChR was increased in the hippocampus.
normalities, such as the loss of presynaptic cholinergic These findings indicate that the subunit-specific markers in the cerebral cortex, are also found in AD brains.
changes in gene expression and the consequent loss of SPs are extracellular structures composed of nicotinic-binding sites are not due to alterations at the congophilic, fibrillar amyloid. There are two major transcription level. PET studies revealed deficits in plaque types: diffuse plaques and neuritic plaques. They nAChRs as early phenomena in AD, stressing the im- are found in AD, and also in some non-demented elderly portance of nAChRs, which is consistent with the patho- persons. Plaques with more amyloid and containing logically predicted data (Perry et al. 2000). Also, more abundant dystrophic neurites are called neuritic nAChRs are considered to be a potential target for drug plaques. In these, the amyloid cores form fibrils staining intervention. The discrepancy between the protein level with thioflavin-S. Neuritic plaques with neurites, both and mRNA level of nAChRs implies that translational and/or posttranslational modification might be damaged mation. CREB, cAMP-regulatory element binding pro- in AD brains. One possibility is the posttranslational tein, is thought to be one of the most important molecu- modification of nAChR by amyloid beta (Ab).
lar components for hippocampus-dependent memoryformation in mammals. From this point of view, block- AMYLOID HYPOTHESIS ON
ade of the association between a7 nAChR and Ab might MEMORY DEFICIT AND nAChR
be a strategy for the treatment of AD.
AD pathology is characterized by SPs which are AMYLOID-INDUCED TOXICITY
composed of Ab. In addition, several mutations found in AND nAChR
familial AD are involved in amyloidogenesis. It hasbeen shown that familial AD mutations in presenilin 1 There is still controversy over the role of Ab in the (PS-1) enhance the generation of Ab1-42, indicating that neuronal loss found in AD brains. However, evidence is PS-1 is involved in amyloidogenesis (Citron et al.
accumulating that Ab causes neuronal death in many 1992). Ab must contribute to the pathogenesis, espe- culture systems. Amyloid accumulation is one of the earliest changes in AD pathology, and this peptide may Walsh et al. (2002) reported that Ab oligomers in- cause neuronal death in the CNS. The precise mecha- hibit hippocampal long-term potentiation (LTP). Ab nism of Ab -induced cytotoxicity remains unknown, al- oligomers, in the absence of monomers and amyloid fi- though various hypotheses have been suggested. It has brils, disrupted synaptic plasticity at concentrations been reported that oxidative stress or free radical gener- found in human brain and cerebrospinal fluid. This phe- ation may mediate Ab -induced cytotoxicity (Behl et al.
nomenon might be one of the major mechanisms of 1994). Ab stimulates nitric oxide (NO) production in memory disturbance found in the early stages of AD.
astrocyte culture (Akama et al. 1998) and also calcium Itoh et al. (1999) showed that nicotinic signaling was entry, triggered by activated N-methyl-D-aspartate impaired in Ab-infused rats using an extracellular re- (NMDA)-gated channels (Le et al. 1995). This might cording technique on hippocampal slices. LTP in CA1 cause peroxynitrite generation and lead to cell death.
pyramidal cells was also impaired in the Ab-infused Other reports suggested that Ab inhibited glutamate up- rats, and it was suggested that this dysfunction may be take (Harris et al. 1996). These reports imply that Ab -induced cytotoxicity might be mediated via glutamate Recently it was reported that Ab, especially fragment toxicity. There are also some reports suggesting that Ab 1-42, binds to a7 nAChR. Binding of Ab inhibits a7 enhances the toxicity induced by excitotoxin (Dornan et nAChR-dependent calcium influx, which could explain al. 1993, Morimoto et al. 1998). We also showed that the cognitive deficit of AD (Wang et al. 2000).
Ab25-35 activity is mediated via NMDA receptors, and Immunocytochemical studies on human sporadic Alz- that Ab1-40 and Ab1-42 enhance glutamate neurotoxicity, heimer's disease brains have demonstrated that Ab1-42 which was mediated via NMDA receptors. An imbal- and a7 nAChR are both present in neuritic plaques and ance in glutamate signals leading to survival or death is co-localize in individual cortical neurons. Ab1-42 and a7 the point of glutamate-induced neuronal death, and Ab nAChR can be co-immunoprecipitated, suggesting that alters this balance to make neurons vulnerable to gluta- they are tightly associated. Receptor binding experi- ments confirmed this association. Human neuro- Nicotinic receptor stimulation inhibits Ab toxicity blastoma cells with a7 nAChR are killed by Ab1-42, and (Kihara et al. 1997, 1998, 2001) and glutamate toxicity nicotine or epibatidine inhibited this death. In addition, (Shimohama et al. 1996), and a7 receptors, in particu- Ab1-42 inhibits a7 nAChR-dependent calcium activa- lar, contribute to PI3K-Akt phosphorylation, which is tion and acetylcholine release, which may be involved important for protection. In addition, the Bcl-2 family exists downstream of the PI3K-Akt cascade and works Dineley et al. (2001) indicated that Ab activated the as an anti-neuronal death factor. Furthermore, nicotine mitogen-activated protein kinase (MAPK) cascade via modulates signal transduction to maintain the PI3K cas- a7 nAChR. Ab-induced activation through a7 nAChR cade which might be down-regulated by Ab . Glutamatemight downregulate the MAPK-CREB phosphorylation also activates the PI3K system, which might protect system, which leads to the dysfunction of memory for- cells from radical formation-induced injury. We hy- AD and ACh receptors 103
pothesized that Ab-induced collapse of this system is (Clark and Karlawish 2003, Kapaki et al. 2003). Four the cause of vulnerability. The precise mechanism re- AChEI have been approved: tacrine (Cognex ), mains unknown, but nicotinic stimulation might up-reg- donepezil (Aricept ), galantamine (Reminyl ), and ulate the PI3K cascade, which would contribute to rivastigmine (Excelon ). These drugs produce the same maintain viability. Ab binds to a7 nicotinic receptors degree of modest improvement in approximately (Wang et al. 2000), which might cause vulnerability be- 30-40% of patients with mild to moderate AD. The ef- cause of the reduction in nicotinic signal transduction.
fect of AChEIs may depend on augmented acetylcho- Also, competitive stimulation of a7 nicotinic receptors line levels. However, it has been reported that might rescue cells from glutamate or NMDA recep- galantamine allosterically modulates nicotinic acetyl- choline receptors in addition to the effect of AChEI Neuronal loss is one of the characteristics of AD pa- (Maelicke and Albuquerque 2000). Direct stimulation thology, and neuronal death may be induced by Ab.
of the nAChR might enhance the improvement of cogni- Stimulation of nAChR could inhibit neuronal death, tion. Recently, it has been shown that donepezil has a which would counter the progress of AD pathogenesis.
protective effect on glutamate-induced neuronal deaththrough a7 nAChR (Takada et al. submitted). In our CLINICAL TRIAL
study, galantamine also exerted a neuroprotective effecton Ab- and glutamate-induced neurotoxicity (Kihara et Cholinergic abnormalities are found in AD brains as de- al. submitted). There may be many more possibilities for scribed above. Bymaster et al. (1993) showed that the these drugs, and some clues might be found for the devel- muscarinic antagonists scopolamine and trihexyphenidyl opment of more effective drugs for the treatment of AD.
bind muscarinic acetylcholine receptors, and that these,but not a nicotinic antagonist, impaired memory perfor- CONCLUSIONS
mance in a spatial alternation task in rats. In particular, ithas been reported that M1 receptors are associated with Cholinergic replacement therapy, using AChEIs, is muscarinic antagonist-induced amnesia. In addition, it has currently available and effective for the treatment of been shown that M1 receptors are involved in memory AD. It is, however, controversial whether acetylcholine processes using M1 receptor mutant mice (Anagnostaras receptor agonists, nicotinic or muscarinic, would im- et al. 2003). Conversely, muscarinic agonists could im- prove the symptoms of AD. Recent data has indicated prove working memory. However, some reports showed that AChEIs possess a nicotinic receptor modulating ef- little effect of muscarinic agonists on memory formation fect, which might enhance the cognition improving ef- fect. Abnormalities of the cholinergic system are Alternatively, it has been reported that nicotinic re- prominent findings in AD, beside senile plaques, ceptor stimulation improves memory. The selective neurofibrillary tangles and neuronal loss. Appropriate cholinergic channel activator (nicotinic agonist), and timely stimulation of acetylcholine receptors is nec- ABT-418, significantly improved recall failure on a ver- essary for the treatment of AD and it is important to bal learning task in AD patients (Potter et al. 1999).
develop such drugs as soon as possible.
Qualitatively similar improvements were seen innon-verbal learning tasks such as spatial learning and ACKNOWLEDGEMENTS
memory, and repeated acquisition. Stimulation of cen-tral nicotinic receptors is shown to have an acute This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of education, Both nicotinic and muscarinic receptors seem to be Culture, Sports, Science and Technology of Japan, and associated with memory disturbance, and stimulation of grants from the Ministry of Health, Labor and Welfare these receptors may be efficacious for the treatment of of Japan and the Smoking Research Foundation.
AD. However, there seems to be many problems to beresolved before an effective stimulant can be developed.
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