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Artículo destacado 
Drug News & Perspectives LOOKING AHEAD It appears that the cholinergic balance is not restricted to neurons and synapses, but may also involve immune reactions. The Role of Cholinergic Balance Perturbation in Neurological Diseases by Eran Nizri, Izhak Wirguin and Talma Brenner Summary The maintenance of a balanced cholinergic homeostasis is crucial for the function of the central nervous system, peripheral nervous system and the neuromuscular junction. However, it appears that the cholinergic system is not restricted to neurons and synapses but may also involve immune reactions. In the present review we reassess the role of the cholinergic balance in myasthenia gravis and Alzheimer's disease which for a long time are known to be associated with cholinergic transmission perturbation. We have included neuroinflammation, particularly multiple sclerosis in this group of neurological disorders in light of the relatively new studies involving the immune cholinergic system. In all the aforementioned disorders, treatment with acetylcholinesterase inhibitors can attenuate inflammation. This is performed by increasing the acetylcholine (ACh) concentration near immune cells and making it available for interaction with α7 nicotinic ACh receptor, expressed on these cells. This outcome is additional to the effect of acetylcholinesterase inhibitors on neurons and synapses. © 2007 Prous Science. All rights reserved. Acetylcholine (ACh) is mainly perceived as a neurotransmitter and, as such, its functions are associated with the nervous system, both central and peripheral. Cholinergic synapses are found, among others, in brain areas associated with cognitive functions, such as the cerebral cortex and hippocampus. It is also responsible for transmission in the peripheral nervous system, including the neuromuscular junction (NMJ), where it mediates motor activation, and in the autonomic nervous system, in which it is responsible for the ganglionic transmission of the entire system and for the postganglionic transmission of the parasympathetic arm. Termination of signaling in the cholinergic system is mediated via ACh degradation by acetylcholinesterase (AChE), the enzyme whose activity determines the duration and the efficacy of cholinergic neurotransmission. This enzyme has several isoforms, both membrane bound and soluble, the product of alternative splicing of its mRNA1. AChE inhibitors (AChEI) are in wide clinical use in myasthenia gravis (MG)2 and in Alzheimer's disease (AD)3. As ACh is also found in the parasympathetic postganglionic synapses, parasympathetic over activity accounts for the majority of side effects which are reported in AChEI treated patients4. It has long been known that components of the cholinergic system are present in immune cells. It turns out that T cells possess a complete cholinergic system, termed "non-neuronal immune cholinergic system5". These cells are able to synthesize ACh due to the expression of the enzyme cholineacyltransferase (ChAT) and can respond to cholinergic signals through various muscarinic and nicotinic receptors (mAChR and nAChR, respectively). Termination of signaling in this system is also mediated by AChE. The presence of the immune cholinergic system, which efficiently responds to the neuron-secreted ACh, may form the basis for neuroimmune interactions6. Alternatively, this system could serve as an internal regulator for immune responses5. It has been shown that the α7 nAChR present on macrophages is an antiinflammatory target. Activation of this receptor, either physiologically by vagal stimulation or pharmacologically with nicotinic agonists, reduced proinflammatory cytokine production and in- creased survival in a severe endotoxemia model6,7. It appears that α7 nAChR activation decreases NF-κB-mediated transcription, and thus may affect the secretion of various other inflammatory mediators8. The same holds for T cells: In these cells as well, activation of α7 nAChR reduced mitogen-induced proliferation and proinflammatory cytokine secretion9. Nevertheless, mAChR activation seems to have a proinflammatory role as activation of this receptor induced c-fos transcription and increased nitric oxide production10. Apparently, the immune cholinergic system does not act unidirectionally, and the specific phenotype exerted by cholinergic signals depends on the summation of all cues in each specific cellular environment9. Thus it appears that the cholinergic balance is not restricted to neurons and synapses, but may also involve immune reactions—both innate and adaptive. In the present review, we reevaluate the role of the cholinergic balance in neurological disorders, such as MG and AD, which for a long time are known to be associated with cholinergic transmission perturbation and neuroinflammation, in light of the relatively new studies involving the immune cholinergic system. Cholinergic transmission is also prevalent in other brain systems, such as the extrapyramidal movement control system with its associated cognitive dysfunction and reward related behavior, two fields which were recently reviewed11,12. However, in these cases, the cholinergic system appears to be intact but out of balance with other synaptic systems, mainly the dopaminergic system, hence these disorders will remain out of the scope of the present review. Cholinergic balance in the peripheral nervous system Of all the cholinergic synapses in the peripheral nervous system, the NMJ is the best characterized site in which immune-mediated or genetic-based disruption of cholinergic transmission occurs as a number of clinical syndromes, the most common of which is MG. MG is a long recognized neurological disorder characterized by excessive muscle fatigability leading to moderate to profound weakness upon exertion. In the majority of cases, the first muscles involved are the extra ocular muscles, leading to ptosis and double vision, which tend to occur and worsen as the day progresses. The next most commonly affected muscle groups are those controlling speech and swallowing producing typical "bulbar" symptoms followed by axial muscles and proximal limb girdle musculature. Respiratory muscle involvement is not uncommon, resulting in life-threatening "myasthenic crises" necessitating intensive care and mechanical ventilation13. Basic neurophysiological and pharmacological studies originating in the first half of the 20th century pointed to malfunction of the NMJ as the underlying cause of the myasthenic weakness. In the NMJ, nerve terminal action potentials are transmitted via a cholinergic synapse to the postsynaptic muscle endplate membrane2. It is now well established that the muscle fatigability is caused by antibody-mediated autoimmunity against the nicotinic NMJ receptor for ACh. This antibody-mediated attack on the NMJ is thought to abolish the naturally occurring "safety factor" of synaptic transmission. The antibodies induce a reduction in the number of available AChR molecules through cross linking and accelerated degradation, and possibly by complement-mediated membrane damage that impairs the secondary activation of voltage-gated sodium channels, which normally act as amplifiers of the end plate potential to create the muscle action potential2. Approximately 15% of patients with MG do not have measurable antibody levels against AChR. A significant proportion of these "seronegative" cases have antibodies directed at the muscle specific kinase (MuSK), an NMJ protein that is associated with the AChR and plays a role in its assembly3. It is virtually impossible to distinguish between AChR antibody-mediated and MuSK antibody-mediated MG on clinical grounds. Another uncommon NMJ syndrome manifesting with myasthenic weakness, usually with coexisting autonomic symptoms is the Lambert Eaton myasthenic syndrome (LEMS). The pathogenesis of LEMS is attributed to the presence of antibodies against the presynaptic p/q voltage-dependent calcium channel which interfere with the release of ACh following nerve terminal action potentials14. Altogether, it is fairly evident that in MG and its related disorders, "cholinergic balance" is impaired at the nicotinic synapse of the NMJ. Both the diagnosis and the symptomatic treatment of MG are based on cholinergic modulation, namely the partial restoration of cholinergic balance by prolongation of the postsynaptic receptor stimulation through AChEI. For the diagnostic test, a short-acting AChEI, edrophonium, is administered intravenously, often producing a dramatic improvement of the weakened muscle force4. Another diagnostic test, often employed for diagnosing MG is the repetitive nerve stimulation test. In this test, the compound muscle action potential (CMAP), which comprises the combined electrical response of all muscle fibers recorded via a surface electrode to repetitive stimuli administered to the nerve supplying the muscle at a low frequency (2-5 Hz). At these stimulation rates, the quantal content of ACh released with each action potential declines gradually by a few percent over subsequent stimuli. While in normal synapses, the safety factor is much larger than the slight reduction of ACh release, resulting in stable transmission throughout the test. In myasthenic synapses progressive failure of some fibers to respond becomes evident, producing the decremental response or gradual reduction of the CMAP amplitude15. Electrodiagnostic studies in LEMS typically show very small CMAPs, decremental responses at low frequency stimulation but significant increments at high frequency stimulation rates (10-50 Hz) which enable a gradual increase in intracellular calcium and subsequently increased quantal release of ACh14. Symptomatic treatment of MG is usually begun with an orally available, noncompetitive AChEI, pyridostigmine. This drug, despite its short half-life and erratic bioavailability, has served as the staple symptomatic therapeutic agent for decades. The amelioration of weakness seen in MG patients treated by AChEI is seldom complete, but in some instances may be sufficient to enable normal life functions without the need for further immunosuppressive treatment4. Side effects of AChEI include muscarinic overactivity symptoms such as abdominal cramps, diarrhea, sweating, nasal discharge, salivation, tearing, increased urination and bradycardia. Another, less common, side effect is increased muscle weakness due to NMJ receptor overstimulation culminating in the development of a curariform (nondepolarizing) block. The resultant weakness may be quite severe, and the differentiation of such a cholinergic crisis from the more common myasthenic crisis can present a serious clinical challenge to the treating physicians. The current management of MG includes the use of AChEI for temporary improvement of neuromuscular transmission, removal of anti-AChR antibodies and the use of nonspecific immunosuppression or immunomodulation2,13. Experimental autoimmune MG (EAMG) is an animal model whose chronic phase closely resembles human MG. It is widely used for studying the human disease including the effect of different pharmacological agents on neuromuscular transmission2,4,16. Previously we found in rats with chronic EAMG, treated with antisense targeted to AChE mRNA for 1 month, significant improvement in survival, clinical status and stamina16. This recuperation was associated with an improvement in immunological parameters. We assume that the antisense treatment normalized neuromuscular transmission and induced a long-term stable cholinergic upregulation that acted both at the NMJ and on the immune cells. This is in light of the new studies regarding the involvement of the non-neuronal immune-cholinergic system in the regulation of immune-mediated reactions. However, it should be noted that clinicians have failed to notice that AChEI exert any immunomodulating effect under clinical settings in MG. There is no evidence to suggest that AChEI have an enhancing or regulating effect on anti-AChR titers and their effect does not linger on for more than a few hours after discontinuation of their use. Despite some cross reactivity between the NMJ AChR, which contains two α1 subunits within its pentameric structure and the autonomic ganglia nAChR, which contain two α3 subunits, involvement of autonomic synapses in MG and related disorders was not recognized until the last decade. Since 1996, anecdotal reports of autonomic failure, mainly intestinal hypomotility, in MG began to appear17,18. Subsequently, a rare autoimmune autonomic neuropathy was characterized, an assay for anti-α3 antibodies was developed and an animal model of experimental autoimmune autonomic dysfunction was established19,20. Clinically the disorder usually manifests acutely or subacutely with severe and even life-threatening autonomic failure, and in some cases it presents as a paraneoplastic disorder associated with the presence of small cell lung cancer. Thus, we are gradually becoming aware that immune-mediated activity may disrupt cholinergic synaptic transmission throughout the peripheral nervous system, producing a fairly wide variety of clinical syndromes. The cholinergic balance in Alzheimer's disease AD is the most common dementia comprising about two-thirds of all diagnosed dementias. It affects as many as 5% of adults aged over 65 years, and up to 50% above 90. Consequently, as life expectancy increases, the burden of AD rises exponentially. Clinically, the cognitive deterioration is manifested as a decline in memory, judgment, language, decision-making and orientation to surroundings21. Pathologically, the disease is characterized by neuronal and synaptic loss in the cortex and hippocampus, both areas associated with cognitive function. Another area which typically degenerates early in the disease is the basal nucleus of Meinert, which is a major source of cortical cholinergic input. Therefore AD is almost invariably associated with a disruption of cholinergic balance. Extracellular plaques containing β-amyloid and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein accompany, and may actually induce, neuronal loss3. There is also prominent activation of astrocytes and microglia near the plaques, attesting to an innate immune response22. Treatment of AD may be directed against each of the components of the pathological process: i) neuroprotective strategies (against neuronal loss); ii) antioxidant and antiinflammatory treatment (against accompanying inflammatory-induced neurotoxicity); iii) external compensation for specific neurotransmitter loss (like AChEI); iv) specific therapy against β-amyloid (halting aggregation or deposition, enhancing clearance) and tau hyperphosphorylation. Actually, treatment is dependent on disease stage: In early stages, centrally acting AChEI are used in an attempt to restore cholinergic input and partially ameliorate the memory loss. Some add to this regimen high dose α-tocopherol (vitamin E) as an antioxidant and neuroprotective agent23. As the disease progresses, behavioral and neuropsychiatric problems arise, mandating specific symptomatic treatment. In the terminal stage, patients suffer from pressure sores, nutritional deficits and eventually succumb to infections such as pneumonia or septicemia.23 As no anti-amyloid therapy is currently available, AChEI constitute the only specific treatment for mild to moderate AD. AChEI and AD-a re-evaluation Several AChEI have been approved for the treatment of mild to moderate AD. These drugs penetrate the blood-brain barrier and act by enhancing cholinergic transmission in brain areas associated with cognitive functions and suffering from neuronal loss. The reduction in ACh breakdown exerted by these drugs allows compensation for the decrease in viable neurons. This treatment is, therefore, a symptomatic treatment with debatable efficacy24,25. It is clear that AChEI only modestly affect disease progression, with a decrease of 2.5 to 3.5 points in the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-Cog)26,27. In any event, two clinical observations suggest that enhancement of cholinergic transmission is not the only mechanism of action of AChEI. The first is that in 20% of AD patients treated with AChEI, cognitive function is stabilized for 24 months. This effect is surprising in light of the symptomatic influence of AChEI treatment. The second is that upon discontinuation of drug treatment, the deterioration in cognitive function returns to the predicted course more slowly. And again, if AChEI were only enhancing cholinergic transmission, deterioration should quickly return to the untreated patients course, since the half-life of AChEI is relatively short.28 Several alternative mechanisms were proposed based on experimental data (Table I): i) AChEI increase the secretion of soluble fragments of amyloid precursor protein (sAPP). This effect is dependent on AChE inhibition and involves activation of M1 and M3 mAChR29. The observation that treatment of AD patients with a selective M1 muscarinic agonist decreased cerebral spinal fluid levels of β-amyloid30 supports this notion. ii) It was shown that AChE is associated with amyloid plaques: the presence of AChE accelerated amyloid fibril formation, and increased the neurotoxicity of the complexes31. It was found that a hydrophobic region close to the peripheral anionic site of the enzyme is responsible for this interaction. Hence, AChEI that bind to this site may prevent the transformation of β-amyloid to amyloid fibril aggregates32.
Recently we suggested a new role for AChEI9,33. We showed that AChEI might serve as antiinflammatory agents by decreasing both T-cell proliferation and proinflammatory cytokine secretion. This property is dependent on α7 nAChR activation, as the addition of an α7 antagonist (α-bungarotoxin) or an antisense oligonucleotide to α7 mRNA abolished this effect. Thus, the mechanism suggested is the following: inhibition of AChE with AChEI slows ACh breakdown, resulting in a higher concentration of ACh, which can subsequently activate the α7 nAChR (Fig. 1). Furthermore, using EN-101, an antisense targeted to AChE mRNA (the same sequence used for EAMG treatment), we demonstrated antiinflammatory properties of AChEI in vivo in a CNS inflammation model (see below). EN-101 as well as conventional AChEI inhibited proinflammatory cytokine secretion34. Is it possible that the effects of AChEI in AD are also connected to the inflammatory process occurring in the course of the disease?
Fig. 1. Suggested model of antiinflammatory outcomes due to cholinergic upregulation during neuroinflammation. Activated T cells sensitized toward the central nervous system (CNS) antigens migrate to the CNS, where an inflammatory reaction that involves the local immune resident cells (astrocytes and microglia) is initiated. This inflammatory cascade is responsible for the demyelination and axonal damage present in multiple sclerosis. Following interaction between soluble and membrane-bound acetylcholinesterase (AChE) and AChE inhibitors (AChEI), the degradation rate of neural and lymphocyte-secreted acetylcholine (ACh) is reduced, leading to cholinergic upregulation. The increased level of ACh interacts with the α7 nicotinic ACh receptor (α7 nAChR), present on macrophages, microglia, astrocytes and T lymphocytes. Signaling through the α7 nAChR is associated with antiinflammatory effects, such as reduced proliferation and proinflammatory cytokine secretion. Thus, increasing the cholinergic signaling via the α7 nAChR could limit the peripheral and central inflammatory process. NMJ, neuromuscular junction; TNF-α, tumor necrosis factor α; IL-1β, interleukin-1β. AD and inflammation As noted above, the brains of AD patients show marked activation of an innate immune response near the amyloid plaques. This activation includes secretion of proinflammatory cytokines like interleukin (IL)-1β and tumor necrosis factor (TNF)-α, activation of complement, and expression of chemokines22. Recently it was shown that there is also a T-cell component in AD-associated inflammation35. Peripheral T cells from elderly and AD patients showed a higher percentage of cells reactive to β-amyloid than those of healthy adults. Moreover, the response to β-amyloid in elderly and AD patients was more pronounced, as judged by the stimulatory index. Phenotypically, reacting T cells were of Th1, Th2 and Th0 lineages. However, it is not clear from this study whether the patients were treated with AChEI, and how the treatment influenced the T-cell phenotype. Thus, the inflammatory process in AD involves T cells, microglia and astrocytes. As mentioned above we have shown that AChEI have an antiinflammatory effects on T cells9. There is evidence that α7 nAChR has similar antiinflammatory effects when expressed on microglia36,37. Astrocytes also express α7 nAChR, and this expression is upregulated in the brains of AD patients38. Preliminary experiments performed in our laboratory indicate that α7 present on astrocytes is also an antiinflammatory target, reducing the secretion of nitric oxide and TNF-α. Therefore, it is possible that AChEI affect astrocytes and microglia in the same way as they affect T cells: increasing the interaction of ACh with α7 nAChR. Thus, AChEI may affect the inflammatory activity of various cell types participating in AD-associated inflammation. Indeed recent reports addressing the cytokine production of peripheral mononuclear cells from AD patients treated with AChEI revealed a Th1 to Th2 switch due to the treatment39,40. These findings strengthen the claim for antiinflammatory activity of AChEI41. By claiming that the beneficial effects of AChEI stem, in part, from their antiinflammatory properties, we assume a detrimental role for inflammation in this disorder. Indeed, inflammation in AD seems to be a double-edged sword. On one hand, activation of the adaptive immune system against β-amyloid, either by active or passive immunization, constitutes a strategy for AD therapy42,43. Further along this line, it was also found that mice deficient in complement activity were affected to a greater extent by amyloid deposits, implicating a beneficial activity of the innate immune system44. On the other hand, it seems that although the primary activation of the immune system is intended to clear the amyloid plaques, when clearance fails, the chronic overactivation of the inflammatory process becomes detrimental22,45,46. Indeed, various epidemiological studies revealed an inverse relationship between the use of antiinflammatory agents and AD45. Despite these findings, clinical trials with nonsteroidal antiinflammatory drugs (both cyclooxygenase-1 and cyclooxygenase-2 inhibitors)47,48 or with prednisone,49 reported negative outcomes. In conclusion, there is no evidence supporting antiinflammatory treatment in AD, although such treatment may still be effective for primary prevention23. The role of cholinergic balance in neuroinflammation, particularly in multiple sclerosis Multiple sclerosis (MS) is considered an autoimmune disease in which T cells are sensitized against myelin components50. When these encephalitogenic T cells enter the CNS they are activated by resident antigen-presenting cells and initiate a cascade of inflammatory damage. The initial inflammatory phase is followed by a phase of selective demyelination and, finally, neurodegeneration50,51. Neurodegeneration is mainly characterized by axonal injury, which begins at disease onset and correlates with the degree of inflammation within lesions. A threshold of axonal loss must be exceeded before irreversible neurological disability occurs52. Clinical manifestations depend on the site of the inflammatory plaque but usually include fatigue, gait disorders, bladder dysfunction and cognitive and affective disorders53. Current MS management consists of classical antiinflammatory agents for acute relapses (corticosteroids), and immunosuppression or immunomodulatory drugs given as maintenance aimed at prevention of relapses and slowing down of disability progression54. There are six treatments approved by the FDA. Three different interferon preparations: Interferon β-1a (Avonex® and Rebif®), interferon β-1b (Betaseron®), glatiramer acetate (Copaxone®), mitoxantrone and natalizumab (Tysabri®)55,56. Experimental autoimmune encephalomyelitis (EAE) is a comprehensive name for a group of animal models used to study human MS,57 and for the study of neuroinflammation and autoimmunity in general. Using the chronic EAE model in C57 black mice we showed recently that treatment with EN-101 reduced clinical and pathological severity and inhibited T-cell reactivity towards the encephalitogenic antigen9. Furthermore, treatment with bifunctional compounds comprising both a cholinergic upregulation moiety (the AChEI pyridostigmine) and a nonsteroidal antiinflammatory moiety (ibuprofen), amelio- rated clinical symptoms in the same EAE model58. The presence of the cholinergic upregulation moiety increased the antiinflammatory effect in the CNS in this model. Cognitive dysfunction in MS Cognitive dysfunction affects half of MS patients and is a major cause of the disability caused by the disease59. Patients suffering from this condition are more likely to be unemployed and to develop subsequently affective disorders, irrespective of their physical disability60. Cognitive dysfunction manifests as impairments in memory, attention, information processing and verbal fluency59. The closest correlation appears to be with brain atrophy rather than with any other imaging parameter59. Despite the abundance of this impairment there is currently no treatment capable of preventing or slowing down its progression61. In general, current treatment strategies rest on pharmacological and nonpharmacological means. Pharmacological treatment can be classified as disease-modifying agents and symptomatic agents, i.e., AChEI or treatment for fatigue. It is postulated that the effectiveness of disease-modifying agents stems from their antiinflammatory and immunomodulatory properties, thus reducing tissue damage and neuronal loss in the brain. Yet, when cognitive performance was assessed in patients receiving disease-modifying treatments, only interferon β-1b proved modest effectiveness61,62, and even these results are obscured by the small number of patients and the possible chance effect of multiple comparisons61. Recently, a randomized controlled trial for treatment of cognitive dysfunction in MS with AChEI was published63. In this trial, 69 patients were treated with donepezil, an AChEI approved for the treatment of AD. Dosage (10 mg/kg) and treatment duration (24 weeks) were as in protocols for AD. The results showed improved performance in the Selective Reminding Test (SRT) for treated patients (p = 0.043), the primary endpoint of the study. Treatment also ameliorated secondary endpoints, such as the patients' report on memory improvement (p = 0.006) and physician reported cognitive improvement (p = 0.036). However, treatment effects could not be demonstrated in other cognitive tests. These findings, together with the small number of patients, impede the applicability of the results. There is no reason that donepezil should ameliorate only one cognitive test, and, again, it may be, a chance result of multiple comparisons. Also, the magnitude of the treatment effect is small (10%)61. The authors do not report any difference in the Expanded Disability Status Scale (EDSS), a clinical score for assessment of MS disease severity, between the two groups upon completion of the treatment, although such a difference existed at baseline. According to our data, we would expect reduced EDSS in the treated group, due to the antiinflammatory effects of AChEI. Clearly, in order to unequivocally prove the effectiveness of this strategy, more research is needed. Although animal models have been successfully used in research on MS, there is no adequate model for recapitulating cognitive dysfunction in this disease. Such a model would allow a study of the mechanisms involved and provide a less expensive and faster modality for testing candidate drugs. Aside from the complexity of testing cognitive function in animal models of learning, EAE raises an additional technical problem. Cognitive function in animals can be analyzed only in animals in the absence of motor activity impairment. However, motor neurological sequelae are part of the manifestations of EAE. A potential way to overcome this obstacle is to use the acute model of EAE, in which animals recover motor function, and then test for cognitive performance64. However, the shortcoming of this strategy is that it uses a specific acute EAE model, which is reminiscent of only one, and clinically milder, MS subtype. Thus, study of cognitive dysfunction in MS poses both experimental and clinical difficulties. However, in light of the antiinflammatory effects of AChEI reported9,58, and the recent trial with AChEI in MS patients suffering from cognitive dysfunction, it seems plausible to suggest treatment of these patients with AChEI. This treatment could prove both disease modifying, due to the antiinflammatory effects of AChEI, and symptomatic, due to the cognitive effects of AChEI (Fig. 2). Of course, such a suggestion awaits experimental and clinical reinforcement.
Fig. 2. The dual effects of acetylcholinesterase inhibitors (AChEI). Attenuation of inflammation and improvement of cognitive deficits. In Alzheimer's disease, a local inflammatory response is present near brain amyloid plaques. Cholinergic upregulation by AChEI improves cognitive function and may also act in downregulation of inflammation by activation of α7 nicotinic acetycholine receptors (α7 nAChR) on immunocompetent cells. In multiple sclerosis, prominent inflammatory lesions lead to demyelination and axonal loss. The cholinergic upregulation exerted by AChEI could be beneficial due to both antiinflammatory outcome that may limit the axonal damage and improvement in cognitive dysfunction. Conclusions Cholinergic balance considerations may be applied to a wider range of neurological disorders. It seems that the cholinergic network can influence various cellular functions such as neurotransmission, as well as immune reactions. In MG and EAMG, neuromuscular homeostasis is impaired due to the destructive effect of autoantibodies directed to proteins involved in signaling at the NMJ. Both diagnosis and symptomatic treatment of MG are based on cholinergic modulation by AChEI. AD is an age-dependent neurodegenerative disorder with prominent activation of inflammatory processes by the innate and adaptive immune response. The cholinergic balance is impaired due to neuronal loss; treatment with special AChEI that penetrate the blood-brain barrier act as compensatory enhancement for cholinergic transmission. In addition, by affecting immunocompetent cells that express the α7 AChR, AChEI may act as antiinflammatory agents and can explain several findings related to the treatment of AD patients with these agents. In MS and EAE, inflammatory T-cell-dependent CNS diseases, demyelination and neurodegeneration follow the initial neuroinflammatory stage. Treatment of MS includes antiinflammatory and immunomodulatory drugs. Treatment with AChEI can induce cholinergic upregulation that subsequently acts via the α7 AChR on immune cells and influences neuroinflammation. These effects are additional to the cognitive benefit gained by the use of these drugs. Thus, neuroinflammation can be added to the list of neurological disorders in which the cholinergic balance can play an important role. Acknowledgments We thank Association Francais counter les Myopathies (AFM) for financial support and Dr. M. Irony-Tur-Sinai for assistance in preparation of this manuscript. References 1. Grisaru, D., Sternfeld, M., Eldor, A., Glick, D. and Soreq, H. Structural roles of acetylcholinesterase variants in biology and pathology. Eur J Biochem 1999, 264(3): 672-86. 2. Conti-Fine, B.M., Milani, M. and Kaminski, H.J. Myasthenia gravis: past, present, and future. J Clin Invest 2006, 116(11): 2843-54. 3. Desai, A.K. and Grossberg, G.T. Diagnosis and treatment of Alzheimer's disease. Neurology 2005, 64(12 Suppl. 3): S34-9. 4. 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