Author: Sean Georgi
Institution: Brigham Young University
Date: February 2005
Over the past decade, researchers have established a definite relationship between Alzheimer's disease and nicotinic acetylcholine receptors (nAChRs). Not only do cholinergic activity and neuronal nAChR levels decrease as the disease progresses, but recent studies have also demonstrated that the beta-amyloid protein produced in Alzheimer's disease can directly and indirectly affect nAChR-mediated synaptic transmission. Researchers are currently trying to elucidate the mechanisms of these effects while simultaneously studying the pharmacological modification of nAChRs by other compounds. It is hoped that new drugs may be able to prevent the negative effects of beta-amyloid in vivo, and thus serve as treatment strategies for Alzheimer's disease. A recently discovered class of compounds that can allosterically potentiate nAChRs has shown great promise as a treatment for Alzheimer's disease, as have subunit-specific agonists. Although both of these can alleviate symptoms and temporarily retard the progression of the disease, they cannot prevent Alzheimer's disease, nor cure it. This paper discusses recent discoveries pertaining to nAChRs and their roles in Alzheimer's disease, as well as nAChR-based treatment strategies.
An important communication pathway in the nervous system involves neurons that respond to and release the neurotransmitter acetylcholine. Two types of acetylcholine receptors exist in the mammalian brain: nicotinic and muscarinic, reflecting their functional response to nicotine and muscarine, respectively. Recent studies have correlated nicotinic acetylcholine receptor (nAChR) dysfunction with the neurodegeneration and cognitive deficits of Alzheimer's disease, epilepsy, schizophrenia and Parkinson's disease (Nashmi et al. 2003).
nAChRs are found peripherally at every motor end plate, as well as centrally. In the brain they are most commonly found in the hippocampus, temporal cortex, and basal forebrain, areas classically considered to be centers of learning and memory. Much less is known about neuronal nAChRs than about those found at the motor end plate.
Current nAChR research studies the characteristics and roles of nAChRs, as well as the ways they are modified by drugs and chemicals. Recent studies have shown that beta-amyloid, a defective protein produced in Alzheimer's patients, can bind to nAChRs and impair their function (Pettit et al. 2001). However, the application of certain compounds can counteract the negative effects of beta-amyloid, suggesting that they could serve as treatments for Alzheimer's disease. In addition, other treatments are currently being researched that compensate for symptoms of Alzheimer's disease by directly modifying nAChRs. However, all drug therapies discovered so far can only alleviate symptoms or temporarily retard the progression of the disease. This paper discusses these and other recent discoveries by surveying current scientific literature in two main areas of nicotinic acetylcholine research: 1) The role that nAChRs play in Alzheimer's disease, and 2) The use of nAChRs as targets for Alzheimer's disease treatments.
This paper shows that while researchers have recently made many significant discoveries in both of these areas, there are still many important questions that need to be answered before a cure for Alzheimer's disease can be developed.
nAChR Structure and Function
A complete nAChR requires five individual subunit proteins to be functional (Figure 1). Researchers have isolated the genes for a number of subunits in mammals, including alpha-2, alpha-3, alpha-4, alpha-5, alpha-6, alpha-7, alpha-9, alpha-10, beta2, beta3, and beta4, as well as for several related subunits in birds and invertebrates (Small and Fodero 2002). Most functional nAChRs contain more than one subunit, and are therefore heteromeric. However, not all combinations of subunits are possible. For example, alpha-5 cannot form a stable nAChR with beta3, and alpha-6 is only stable when combined with beta3 and at least one other subunit. The major heteromeric nAChR found in the nervous system is alpha-4-beta2, which most likely contains two alpha-4 subunits and three beta-2 subunits. In contrast, alpha-7, alpha-8, and alpha-9 can form homomeric receptors containing only one type of subunit. Indeed, another major type of nAChR in the nervous system is the alpha-7 homomeric pentamer (Guan et al. 2000).
The binding site for acetylcholine is located where alpha- subunits form junctions with neighboring subunits (Figure 1). Thus, a functional nAChR could potentially bind more than one molecule of acetylcholine simultaneously. Once at least two acetylcholine molecules are bound, the nAChR changes conformation to open a central pore. This pore allows cations such as Na+ and Ca2+ to enter the cell until the pore re-closes.
While each subunit differs in its amino acid sequence, the overall tertiary structure is similar. All nAChR subunits cross the cell membrane four times and have large intracellular loops (Figure 2). The N and C termini of all subunits are on the extracellular side of the membrane. The second transmembrane region (M2) lines the central pore of the receptor.
alpha-7 homomeric receptors differ from alpha-4-beta-2 heteromeric receptors in several respects. For example, alpha-7 nAChRs are desensitized faster than alpha-4-beta-2 nAChRs. In addition, alpha-7 nAChRs can be activated by choline and are blocked by two neurotoxins: alpha-bungarotoxin and methyllycaconitine (MLA). alpha-4-beta-2 nAChRs are not activated by choline, and are not affected by alpha-bungarotoxin or MLA. Instead, they can be blocked by dihydro-beta-erythroidine (DH-beta-E), another toxin (Nashmi et al. 2003). These differences allow researchers to determine what types of receptors are present in a cell by comparing responses to these different drugs.
Another important difference is that alpha-7 homomeric nAChRs are more permeable to Ca2+ than alpha-4-beta-2 nAChRs, suggesting that in vivo they are involved in calcium regulation and intracellular signaling. These two processes may play a vital part in long-term potentiation, an important element in memory formation (Maelicke et al. 2000, Frier and Herron 2003).
Physiologic Role of nAChRs in the CNS
The physiologic role of nAChRs in the central nervous system is not completely clear, but they are thought to play vital roles in the processes of memory and learning, as well as in attention, arousal, and sensory perception. Areas of the brain classically considered centers of memory formation and storage are rich in nAChRs. Nicotine and other nAChR agonists enhance learning and memory in animals, while lesions in areas rich in nAChRs impair memory formation (Grutzendler and Morris 2001).
While neurotransmitter receptors are usually found on the dendrites of neurons, recent discoveries show that nAChRs are also found on axons. In this way, an electrical signal does not have to travel down the dendrites and cell body to affect neurotransmitter release. Rather, the signal is produced directly in the axon, bypassing the dendrites and cell body altogether, which is a faster and more direct means of presynaptic control. The majority of cognitive functions governed by nAChRs are probably mediated by these "presynaptic" nAChRs rather than those found postsynaptically (Bourin et al. 2000).
nAChR Synthesis and Regulation
Very little is known about the synthesis and regulation of nAChRs. Chronic nicotine administration to animals induces a nAChR upregulation in the brain. Similarly, smokers have increased nAChR levels. While the mechanisms of this upregulation are not well understood, nicotine likely does not increase the transcription of nAChRs subunit genes, but rather increases nAChR assembly in the cell body and subsequent export to the dendrites (Nashmi et al. 2003). This nicotine-induced upregulation of nAChR levels may simulate an undiscovered natural regulatory mechanism. Further research into this mechanism may prove beneficial to nAChR-related diseases, such as Alzheimer's disease.
nAChRs and Alzheimer's Disease
Alzheimer's Disease is a progressive neurodegenerative disorder that primarily affects the elderly and accounts for 70% of all dementia. Between 17 and 25 million people worldwide currently suffer from Alzheimer's disease, a number that is estimated to quadruple in the next 50 years. While only 1% of adults between the ages of 60 and 64 suffer from Alzheimer's disease, nearly 50% of those over the age of 85 have the disease (Scott and Goa 2000, Zarotosky et al. 2003).
Those with Alzheimer's disease display a progressive deterioration of memory and cognitive function that eventually leads to severe dementia and death. Symptoms can also include impaired attention, language disturbances, and emotional instability. Most patients diagnosed with Alzheimer's disease eventually end up in nursing homes and impose a large financial burden on the government, as well as on the families of the patients. In the United States alone, Alzheimer's disease related expenses surpass $100 billion every year, or $195,000 per patient (Scott and Goa 2000, Zarotosky et al. 2003).
While the ultimate causes of Alzheimer's disease are not known, there are several distinguishing neurological changes that correlate with the typical symptoms. The brains of those with Alzheimer's disease display significant deterioration, especially in those areas responsible for memory and learning. In one study, the nucleus basilis (part of the basal forebrain) of Alzheimer's disease patients contained five to six times fewer neurons than those of people not affected by the disease (Giacobini 2003). Due to the nature of the deterioration in Alzheimer's disease, a definite diagnosis can only be done by biopsy of brain tissue or during an autopsy (Scott and Goa 2000).
In addition to significant neurodegeneration, the brains of Alzheimer's disease patients display an abnormal accumulation of amyloid plaques. These are insoluble aggregates of protein that are toxic to neurons. The major constituent of these plaques is the protein beta-amyloid.
In Alzheimer's disease there is also an abnormal appearance of neurofibrillary tangles (Figure 3). These are tangles of the intracellular protein tau that has become hyperphosphorylated, causing it to dissociate from microtubules and clump together. Because tau normally stabilizes microtubules, this dissociation results in microtubule instability and subunit detachment (Wang et al. 2003).
The Cholinergic Hypothesis
In the late 1970s and early 1980s research indicated that another major feature of Alzheimer's disease is decreased cholinergic (acetylcholine-based) activity in the brain. In addition, it was found that patients with Alzheimer's disease had up to a 90% decrease in acetylcholinesterase and choline acetyltransferase activity. These two enzymes are respectively involved in the degradation and synthesis of acetylcholine. This eventually led to the cholinergic hypothesis of geriatric memory dysfunction, which proposed that the cognitive deficits in Alzheimer's disease result from this loss of cholinergic transmission (Small and Fodero 2002). It is now recognized that while this loss of cholinergic transmission in the brain plays an important part in Alzheimer's disease, it is not the only factor involved. There are also abnormalities in glutamatergic, noradrenergic, serotonergic, and dopaminergic transmission (Doggrell and Evans 2003). Interestingly, there are no significant changes to muscle nAChRs or muscarinic acetylcholine receptors in patients with Alzheimer's disease.
Although neuronal cholinergic transmission as a whole is reduced in Alzheimer's disease, the specific changes in nAChR expression have been a controversial topic among scientists, especially when considering alpha-7 homomeric receptors. Studies have indicated a range of alpha-7 receptor loss ranging from 17% to 50%. Estimates of the loss of alpha-4-containing receptors in Alzheimer's disease are more consistent, all around 30-40% (Wevers et al. 1999, Banerjee et al. 2000, Guan et al. 2000). Studies have also indicated losses of alpha-3-containing receptors in Alzheimer's disease, but no changes in beta-2 have been noted (Guan et al. 2000).
Studies have correlated the loss of nAChRs in the brain with the severity of Alzheimer's disease symptoms at the time of death (Scott and Goa 2000). However, it has been noted that learning deficits can be present even before any observable cell loss, suggesting that the initial disruption of cognitive function in Alzheimer's disease is not due to cell death, but rather due to the disruption of nAChR receptors, synaptic transmission, or intracellular signaling (O'Neill et al. 2002). Recent theories suggest that the loss of nAChRs as well as their functional disruption may be caused by the protein beta-amyloid.
Beta-amyloid and Alzheimer's Disease
Because beta-amyloid containing plaques are hallmarks of Alzheimer's disease, a great deal of research has been done to understand the beta-amyloid protein and its effects on neurons and neuronal communication. Beta-amyloid is derived from another protein, the amyloid precursor protein (APP), which is found throughout the body, but whose physiologic function is still unknown. In Alzheimer's disease, APP is cleaved proteolytically to form Beta-amyloid, of which there are two main forms: beta-amyloid1-40 and beta-amyloid1-42 (Dineley et al. 2002). While beta-amyloid1-40 is the predominant form of the protein, it is not as fibrillogenic or neurotoxic as beta-amyloid1-42 (Dineley et al. 2002, Grassi et al. 2003). Throughout the remainder of the paper, the term beta-amyloid will refer to beta-amyloid1-42, unless noted otherwise.
Several studies suggest that beta-amyloid interacts with nAChRs. For example, beta-amyloid is predominantly located in areas of the brain that express nAChRs, and neurons that express alpha-7 nAChRs are preferentially killed by beta-amyloid. Beta-amyloid and alpha-7 also co-localize in amyloid plaques (Wang et al. 2000, Grassi et al. 2003). Research has suggested that alpha-7 receptors facilitate the cellular internalization of beta-amyloid proteins (Bourin et al. 2000). In addition to these findings, research has shown that beta-amyloid can directly affect nAChRs by binding to them, as well as indirectly affect their function by interacting with other proteins or with the cell membrane.
Direct Effects of Beta-amyloid
The direct molecular interaction of beta-amyloid with nAChRs has been a source of recent scientific interest. Pettit et al. (2001) showed that beta-amyloid inhibits both whole cell and single-channel nicotinic currents in individual rat hippocampal interneurons by directly binding to and blocking nAChRs. Furthermore, beta-amyloid binds to alpha-7 homomeric nAChRs very tightly, 5000 times more tightly than to alpha-4-beta-2 heteromeric nAChRs (O'Neill et al. 2002). Beta-amyloid also binds to alpha-7 homomeric nAChRs 1000 times more tightly than alpha--bungarotoxin, a very potent and deadly neurotoxin (Grassi et al. 2003).
Contrasting the results above, beta-amyloid activates rather than blocks alpha-7 nAChRs under certain conditions, including low concentrations (Dineley et al. 2002, Dougherty et al. 2003). Fu and Jhamandas (2003) obtained similar results using cells expressing only non-alpha-7 nAChRs. It is possible that this chronic activation is a mechanism by which beta-amyloid induces apoptosis. Chronic stimulation of nAChRs may disrupt intracellular calcium levels, signaling the cell to kill itself (Dineley et al. 2002). The actual effects of beta-amyloid in vivo must be determined before a cure for Alzheimer's disease can be developed
Several studies indicate that incubation with nicotine or other nAChR agonists, including cytisine and DMXBA, protects cultured cells from beta-amyloid-induced apoptosis (Wang et al. 2000, Frier and Herron 2003). However, the mechanism of this is not well understood.
Indirect Effects of Beta-amyloid
In addition to binding directly to nAChRs, beta-amyloid induces lipid peroxidation and free radical formation, leading to cell membrane damage and oxidative stress that may impair nAChR function. The mechanism of these effects is not yet understood, however, pretreatment with an antioxidant is known to prevent them (Guan et al. 2003, Yu et al. 2003).
There is also a correlation between beta-amyloid and the other major hallmark of Alzheimer's disease: hyperphosphorylated tau fibrillary tangles. Using cells expressing alpha-7 nAChRs, Wang et al. (2003) observed that beta-amyloid could induce tau phosphorylation through several intracellular signaling pathways due to an interaction with the alpha-7 nAChRs. Interestingly, this phosphorylation happened only in cells that had been previously subjected to oxidative stress. Wang et al. also observed that a small beta-amyloid fragment (amino acids 12-28) could prevent Beta-amyloid from inducing tau phosphorylation, suggesting that it is this specific part that interacted with the nAChRs.
Hyperphosphorylation of tau causes it to form aggregates and to become dysfunctional. Because the tau protein is normally involved in intracellular transport of proteins, it is possible that the loss of nAChR expression in beta-amyloid-affected cells may be partially due to an inefficient or hindered transport of nAChR proteins to the cell membrane (Wevers et al. 1999).
While much has been learned in the past five years about the direct and indirect effects of beta-amyloid on nAChRs, there are still many unresolved questions. It is not understood why beta-amyloid forms in the first place, nor why it targets only certain nAChRs. Very little is known about the mechanisms by which it kills neurons, nor about its direct and indirect effects on nAChRs. Indeed, some studies have even given contradictory results depending on the specific conditions employed. Many of these questions will need to be answered before a cure for Alzheimer's disease can be developed.
Drugs and Therapeutics for Alzheimer's Disease
Currently, there are no cures for Alzheimer's disease, and nothing has been developed that can directly target beta-amyloid or prevent it from binding to nAChRs. Because progression of the disease can only be slowed, but not stopped, current drug therapies focus on alleviating symptoms by replacing lost cholinergic activity or modifying the remaining cholinergic systems. Current approaches to Alzheimer's disease treatment include acetylcholinesterase inhibitors, whereas future treatments may include cholinergic precursors, cholinergic agonists such as nicotine, and newly discovered allosteric potentiators.
Acetylcholinesterases are enzymes in cholinergic synapses that degrade acetylcholine molecules. Recent therapies for Alzheimer's disease have focused on chemical compounds that bind to and deactivate acetylcholinesterases, thus compensating for post-synaptic receptor loss with a higher level of synaptic acetylcholine. Theoretically, this allows nAChR-containing neurons to continue communicating despite their nAChR loss by prolonging any acetylcholine signal in the synapse.
Acetylcholinesterase inhibitors have been successful and there are currently several such drugs on the market in the U.S., including Tacrine, Rivastigmine, and Donepezil. While these drugs can be beneficial for those suffering from mild and moderate Alzheimer's disease, they cannot prevent progression of the disease. Rather, acetylcholinesterase inhibitors function by temporarily alleviating the symptoms of Alzheimer's disease. Because acetylcholine transmission is not affected in muscles, these drugs may lead to an overstimulation of cholinergic systems outside of the brain and cause a variety of side effects including nausea, vomiting, anorexia, diarrhea, bradycardia, muscle cramping, weakness, nightmares, insomnia, and agitation (Grutzendler and Morris 2001).
Because acetylcholinesterases continuously degrade acetylcholine that is released into the synapse, cholinergic neurons must constantly synthesize acetylcholine to maintain a store of acetylcholine-containing vesicles. Cholinergic precursors are chemicals that are used to synthesize acetylcholine in neurons, and they can theoretically induce increased synthesis of acetylcholine, thus compensating for lost cholinergic activity. A similar method has been very successful in alleviating the symptoms of Parkinson's disease caused by a loss of dopamine. Unfortunately, this therapy has not yet been as successful in Alzheimer's disease. Its major limitation is the fact that it can only be effective where cholinergic neurons are still present. While early cholinergic precursors showed little or no benefit, a recently developed drug, choline alfoscerate, increases the release of acetylcholine in the rat hippocampus, and facilitates learning and memory in animals. While a Mexican study showed that choline alfoscerate could be an effective treatment for Alzheimer's disease, it is not yet on the market in the U.S., and its future use may be limited due to the current success of other Alzheimer's disease drugs (Doggrell and Evans 2003).
Nicotine (Figure 4) activates and binds to nicotinic receptors, and is therefore considered a nAChR agonist. As noted previously, nicotine can prevent beta-amyloid induced apoptosis in cultured neurons. It could theoretically do the same in smokers, thus protecting them against Alzheimer's disease, but the effects of other chemicals found in cigarette smoke have not been evaluated. Indeed, early studies in Alzheimer's patients have suggested that nicotine administration may be beneficial. Studies linking Alzheimer's disease and cigarette smoking have not yet reached a consensus, however. Whereas some studies have indicated that smokers have a lower risk of developing Alzheimer's disease (Maelicke et al. 2000), others have made the opposite conclusion (Sabbagh et al. 2002, Frier and Herron 2003).
Molecular studies have been equally contradictory. Nicotine administration correlates with reduced amyloid plaque deposition and the breakdown of previously formed plaques. Furthermore, while nicotine can improve learning and accuracy in animals, cellular studies have indicated that it amplifies the negative effects of beta-amyloid on long-term potentiation, an essential process for memory formation (Doggrell and Evans 2003, Frier and Herron 2003). Nicotine has not yet been approved as a treatment for Alzheimer's disease, most likely because its effects are not yet fully understood.
Other nAChR Agonists
While the effects of nicotine on the central nervous system are not fully understood, it is clear that it has negative side effects elsewhere in the body. As with acetylcholinesterase inhibitors, nicotine can affect muscle nAChRs as well as the heart and circulatory system. Researchers are currently searching for subunit-specific agonists whose effects would be limited to the brain.
DMXBA, an alpha-7-specific agonist, is currently being tested (Figure 4). Studies have indicated that DMXBA protects against beta-amyloid toxicity as well as promotes the survival of neurons that have been deprived of neuronal growth factor. Tests have further shown that it can enhance cognition in animals. Unfortunately, while selectively stimulating alpha-7 receptors, it may also antagonize alpha-4-beta-2 nAChRs (Kern 2000). In addition, DMXBA was neurotoxic when applied in high concentrations (Bourin et al. 2000).
One major drawback of nearly all nAChR agonists, including nicotine, is nAChR desensitization. As a receptor is stimulated repeatedly, it eventually becomes desensitized. When a receptor is desensitized, it is less likely to open in response to repeated stimulation. High concentrations of agonists may therefore lead to desensitization and have the opposite effect of that desired in Alzheimer's patients (Maelicke et al. 2000). Before they can be effectively used as treatments for Alzheimer's disease, this problem must be overcome.
nAChR Allosteric Potentiators
All of the drugs discussed thus far act by increasing nAChR pore opening, either by increasing the level of acetylcholine in the synapse, or by directly stimulating the nAChRs. Because nAChR levels are decreased in Alzheimer's disease, these drugs try to compensate for this loss by giving more stimulation to those that are still present. However, this extra stimulation can have severe side effects elsewhere in the body, and can eventually lead to desensitization and decreased response. Researchers have recently discovered a novel class of compounds called allosteric potentiators that do not have these same problems, suggesting that they may soon replace other drugs as the treatment of choice.
Like nAChR agonists, allosteric potentiators bind to or otherwise directly interact with nAChRs. However, allosteric potentiators do not elicit pore opening by themselves. Rather, allosteric potentiators increase the response and sensitivity of nAChRs (potentiate them) to agonists, including acetylcholine (Maelicke et al. 2000). Because allosteric potentiators only amplify the signals already being produced, they do not cause desensitization and have fewer side effects than other treatment strategies.
Galantamine (Figure 4), a naturally occurring chemical derived from daffodil bulbs, was recently placed on the market and has showed promising results. Galantamine has been successful because it has two effects on cholinergic synapses: it can act as both an allosteric potentiator and as an anticholinesterase. Studies have found that Alzheimer's disease patients who take galantamine daily show significant cognitive symptom improvement and a reduced requirement for caregiver assistance. In the long-term, galantamine seems to slow progression of the disease and has only minor side effects (Scott and Goa 2000). It is not, however, a cure, because it cannot prevent the disease, nor stop it from killing those who have it.
In addition to galantamine other compounds have been recently discovered that may work by similar mechanisms to allosterically potentiate nAChRs. Certain albumins can be used in this way and can even overcome the effects of Beta-amyloid (Conroy et al. 2003). This discovery suggests that an entirely new type of Alzheimer's drug based on these compounds may soon be on the market.
In addition to the major drug therapies listed above, several other strategies have been suggested as treatments for Alzheimer's disease. Recent studies in rodents have shown that immunization against beta-amyloid may ameliorate symptoms, but such an approach has not yet been taken in humans. A drug called propentophylline promotes the release of nerve growth factor (NGF) in the brain, which may help protect against beta-amyloid-induced cell death. Another drug, levocarnitine, stimulates the enzyme acetylcholine transferase, thus inducing greater acetylcholine synthesis (Grutzendler and Morris 2001).
Recent research findings have alluded to other potential therapeutic strategies for Alzheimer's disease that have not yet been tested or developed. As was discussed previously, some of the adverse effects of beta-amyloid may be mediated by free radical formation (Guan et al. 2003, Yu et al. 2003). This suggests that application of antioxidants, such as vitamin E, may prove beneficial in the prevention of Alzheimer's disease. In addition, the specific amino acid sequence of beta-amyloid that binds to nAChRs has been determined, suggesting that chemical analogues could be synthesized that mimic beta-amyloid and prevent it from binding to nAChRs. Most of these therapies are only theoretical, however.
Every Alzheimer's disease therapy mentioned so far is limited in its effects. Even promising drugs such as allosteric potentiators can only temporarily alleviate symptoms. In the end, all drugs lose their efficacy as Alzheimer's disease continues its progression. A cure for Alzheimer's disease would need to prevent the disease all together, or stop its progression. So far, nothing has been discovered that can do this. Important issues must be addressed before a cure can be developed, such as how to prevent the direct and indirect effects of beta-amyloid on nAChRs, how to stop beta-amyloid from killing neurons, how to prevent beta-amyloid formation, as well as how to target only those nAChRs that are affected in Alzheimer's disease. Much more needs to be learned to produce a cure for Alzheimer's disease.
While recent research has elucidated and solidified the relationship between nicotinic acetylcholine receptors and Alzheimer's disease, there is still much to learn. Indeed, the initial causes of the disease, such as the abnormal formation of beta-amyloid, as well as the mechanisms by which it affects neurons and nAChRs, are still not fully understood. Nor is it understood how the disruption of cholinergic pathways produces the cognitive deficits of Alzheimer's disease. Without such knowledge, the development of a cure is nearly impossible.
Because beta-amyloid disrupts the function of nicotinic acetylcholine receptors, they are logical targets for Alzheimer's disease drugs. Recent research has discovered new strategies that target nAChRs for treating the disease. Specifically, allosteric potentiators such as galantamine may soon replace current treatment strategies because they have fewer side effects. In addition, subunit-specific agonists promise protection against beta-amyloid toxicity, but those currently researched have many problems.
While drugs that affect nAChRs can alleviate symptoms of Alzheimer's disease, they cannot prevent the disease nor stop its progression. Recent advances have been made in understanding the role that nAChRs play in Alzheimer's disease, but much more needs to be learned and many questions need to be answered before a cure for Alzheimer's disease can be developed.
The author thanks Dr. Beverly Zimmerman and Dr. Sterling Sudweeks of Brigham Young University for their help and suggestions.
Banerjee, C. et al. (2000). Cellular Expression of alpha-7 Nicotinic Acetylcholine Receptor Protein in the Temporal Cortex in Alzheimer's and Parkinson's Disease-- A Stereological Approach. Neurobiology of Disease 7, 666-672.
Bourin, M. et al. (2000). Nicotinic receptors and Alzheimer's disease. Current Medical Research and Opinion 19, 169-177.
Conroy, W. et al. (2003). Potentiation of alpha-7-Containing Nicotinic Acetylcholine Receptors by Select Albumins. Molecular Pharmacology 63, 419-428.
Dineley, K. et al. (2002). Beta-Amyloid Peptide Activates alpha-7 Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes. The Journal of Biological Chemistry 277, 25056-25061.
Doggrell, S. and S. Evans (2003). Treatment of dementia with neurotransmission modulation. Expert Opinion on Investigational Drugs 12, 1633-1654.
Dougherty, J. et al. (2003). Beta-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex. The Journal of Neuroscience 23, 6740-6747.
Frier, D. and C. Herron (2003). Nicotine Enhances the Depressive Actions of ABeta1-40 on Long-Term Potentiation in the Rat Hippocampal CA1 Region In Vivo. Journal of Neurophysiology 89, 2917-2922.
Fu, W. and J. Jhamandas (2003). Beta-Amyloid Peptide Activates Non-alpha-7 Nicotinic Acetycholine Receptors in Rat Basal Forebrain Neurons. Journal of Neurophysiology 90, 3130-3136.
Giacobini, E .(2003). Cholinergic function and Alzheimer's disease. International Journal of Geriatric Psychiatry 18, S1-S5.
Grassi, F. et al. (2003). Amyloid Beta1-42 peptide alters the gating of human and mouse alpha--bungarotoxin-sensitive nicotinic receptors. The Journal of Physiology 547, 147-157.
Grutzendler, J. and J. Morris (2001). Cholinesterase Inhibitors for Alzheimer's Disease. Drugs 61, 41-52.
Guan, Z. et al. (2000). Decreased Protein Levels of Nicotinic Receptor Subunits in the Hippocampus and Temporal Cortex of Patients with Alzheimer's Disease. Journal of Neurochemistry 74, 237-243.
Guan, Z. et al. (2003). Loss of Nicotinic Receptors Induced by Beta-Amyloid Peptides in PC12 Cells: Possible Mechanism Involving Lipid Peroxidation. Journal of Neuroscience Research 71, 397-406.
Kern, W. (2000). The brain alpha-7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21).. Behavioural Brain Research 113, 169-181.
Maelicke, A. et al. (2000). Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer's disease. Behavioural Brain Research 113, 199-206.
Nashmi, R. et al. (2003). Assembly of alpha-4Beta2 Nicotinic Acetylcholine Receptors Assessed with Functional Fluorescently Labeled Subunits: Effects of Localization, Trafficking, and Nicotine-Induced Upregulation in Clonal Mammalian Cells and in Cultured Midbrain Neurons. The Journal of Neuroscience 23, 11554-11567.
O'Neill, M. et al. (2002). The Role of Neuronal Nicotinic Acetylcholine Receptors in Acute and Chronic Neurodegeneration. Current Drug Targets. CNS and Neurological Disorders 1, 399-411.
Pettit, D. et al. (2001). Beta-Amyloid1-42 Peptide Directly Modulates Nicotinic Receptors in the Rat Hippocampal Slice. The Journal of Neuroscience 21(RC120)., 1-5.
Sabbagh, M. et al. (2002). The nicotinic acetylcholine receptor, smoking, and Alzheimer's diease. Journal of Alzheimer's Disease 4, 317-325.
Scott, L. and K. Goa (2000). Galantamine: A Review of its Use in Alzheimers Disease. Drugs 60, 1095-1122.
Small, D. and L. Fodero (2002). Cholinergic regulation of synaptic plasticity as a therapeutic target in Alzheimer's disease. Journal of Alzheimer's Disease 4, 349-355.
Wang, H. et al. (2000). Beta-Amyloid binds to alpha-7 Nicotinic Acetylcholine Receptor with High Affinity. Journal of Biological Chemistry 275, 5626-5632.
Wang, H. et al. (2003). alpha-7 Nicotinic Acetylcholine Receptors Mediate Beta-Amyloid Peptide-induced Tau Protein Phosphorylation. Journal of Biological Chemistry 278, 31547-31553.
Wevers, A. et al. (1999). Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer's disease: histotopographical correlation with amyloid plaques and hyperphosphorylayed-tau protein. The European Journal of Neuroscience 11, 2551-2565.
Yu, W. et al. (2003). Correlation of oxidative stress and the loss of the nicotinic receptor alpha4 subunit in the temporal cortex of patients with Alzheimer's disease. Neuroscience Letters 338, 13-16.
Zarotosky, V. et al. (2003). Galantamine hydrobromide: An agent for Alzheimer's disease. Americal Journal of Health-System Pharmacists 60, 446-452.