Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Acetylcholinesterase

  • Benjamín Pérez-Aguilar
  • Cecilio J. Vidal
  • José Luis Gomez-Olivares
  • Monserrat Gerardo-Ramirez
  • Ma. Concepción Gutiérrez-Ruiz
  • Luis E. Gomez-Quiroz
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101486

Synonyms

Historical background

Since its discovery in 1914, acetylcholinesterase (AChE) has attracted attention of many research groups, making AChE one of the most studied proteins. The great physiological relevance of AChE has prompted exhaustive research to know its substrate preference, catalytic mechanism, sensitivity to inhibitors, active site topology, entrance and exiting of substrates, inhibitors and products, and other aspects of AChE-related catalysis (Dale 1914; Brown et al. 1936; Augustinsson and Nachmansohn 1949; Katz 1966; Nachmansohn and Neumann 1975; Rosenberry 1979; Schwarz et al. 1995). The studies regarding kinetic properties of AChE were followed by others to throw light into chromosome mapping, gene expression, mRNA splicing and translation of AChE proteins, polymerization and transport to cell stores, and localization of AChE molecules in tissues and cells (Sussman et al. 1991; Massoulie et al. 1993; Legay 2000; Soreq and Seidman 2001; Massoulie 2002; Meshorer and Soreq 2006).

The relationship of cholinesterases (ChEs) with anti-ChE poisons and through them pharmacology started toward mid-nineteenth century, when the alkaloid physostigmine (also called eserine) was synthesized in the lab. Physostigmine is a carbamate-derived compound which inhibits acetyl- and butyrylcholinesterase activities in a strong and reversible manner, but it fails in inhibiting other esterases. In studies aimed to assess the proteins responsible for ACh hydrolysis, Sir Henry Dale discovered that physostigmine was able to inhibit the activity of an enzyme which exhibited a great capacity for blocking the effects of acetylcholine (ACh) and other choline-esters (Dale 1914). Since then, AChE has been thoroughly examined by a vast number of eminent scientists. As the result, a wealth of information has been built, which includes from catalytic properties to molecular basis of the complex polymorphism that AChE displays, secreted and membrane-linked AChE components, specific actions of individual AChE molecules and their relationship with brain and muscle diseases.

Despite this wide and deep knowledge, AChE continues being a principal matter of study owing to its relevance in cholinergic signaling and downstream response of ACh-sensitive cells and tissues. Nowadays, AChE continues providing unexpected results and broadening current knowledge in many aspects of AChE catalysis and cell biology, including cholinergic and noncholinergic actions, cell localization of separate AChE components, and their involvement or contribution to pathologies.

Mechanism of Action

Acetylcholinesterase is a serine hydrolase that cleaves choline esters rapidly, preferentially acetylcholine (ACh). AChE shows a great ACh-hydrolyzing capacity, and in the list of enzymes classified according to their catalytic efficiency AChE occupies the second position. AChE functions at the limit allowed by substrate diffusion and it can hydrolyze 25,000 molecules of ACh per second and active site (Quinn 1987; Taylor and Radic 1994). This tremendous catalytic capacity has to be multiplied by 2 in AChE dimers, and by 4, 8, or 12 in protein assemblies made of one, two, or three tetramers bonded to a structural protein.

Kinetic studies indicate that AChE is a serine hydrolase which destroys ACh by forming an intermediate acetyl-enzyme and free  choline. The active site of AChE comprises two subsites: (1) the esterase subsite; and (2) the anionic subsite (Fig. 1) (Nachmansohn and Wilson 1951; Sussman et al. 1991; Sussman et al. 1993). The esterase subsite contains a catalytic triad consisting of Ser200, His440, and Glu327. This Glu residue is needed for enhancing the nucleophilic behavior of the Ser residue, which otherwise would be unable to accept the acetyl group of ACh (Sussman et al. 1991). The acetyl-enzyme, which holds the acetyl group bonded to the catalytic Ser, rapidly undergoes a nucleophilic attack by water, a His-assisted step, to liberate acetate. By this way, the catalytically competent AChE protein with unoccupied Ser is regenerated (Soreq and Seidman 2001; Pohanka 2011). The anionic subsite interacts with ACh by binding the quaternary amine group (with positive charge) of the choline moiety. The anionic subsite is defined by Trp84, Phe330, and Phe331. Cationic substrates do not bind to the anionic subsite through negatively charged amino acids. Instead, they interact transiently with 14 aromatic amino acids that line the catalytic “gorge” wall and form an “aromatic guide.” This guide directs the positively charged substrate ACh to the bottom of the gorge where the hydrolytic esterase subsite resides (Radic et al. 1992; Sussman et al. 1993; Ordentlich et al. 1995; Ariel et al. 1998). Among the aromatic amino acids, Trp 84 is critical for catalysis (Sussman et al. 1991; Ordentlich et al. 1993; Dvir et al. 2010). Besides the two subsites of the catalytic center, AChE contains another binding site for ACh and quaternary ligands. This site is called peripheral anionic site (PAS) (Taylor and Lappi 1975).
Acetylcholinesterase, Fig. 1

Catalytic site of AChE. ES esterase subsite, AS anionic substrate binding subsite. Note that ACh occupies both esterase and anionic subsites of the catalytic pocket. The hydroxyl group of the Ser side chain is shown within the esterase subsite. PAS peripheral anionic site

The AChE Gene, Alternatively Spliced Transcripts and Their Encoded Proteins

In humans the AChE gene maps to chromosome 7q22, occupies 7 kb, and includes six exons and four introns (Getman et al. 1992). The 3′-splicing generates three different AChE transcripts. The transcript which includes intron 4 and exon 5 yields the AChER (readthrough) subunit (Fig. 2a). AChER has a short C terminus and lacks a Cys residue, which is needed for oligomerization. As a result, AChER seems to be monomeric and soluble in an aqueous milieu (Fig. 2c). AChER protein has been identified in mammalian and human brains (Kaufer et al. 1998; Soreq and Seidman 2001; Meshorer et al. 2002; Massoulie 2002).
Acetylcholinesterase, Fig. 2

ACHE gene, alternative splicing, and protein products. (a) Structure of the human ACHE gene (drawn to the same scale). Exons are depicted as cylinders, introns as horizontal lines. Splicing options are shown as lines above the genes. 4′ indicates the pseudo-intron 4 (in yellow). (b) Combinatorial complexity of human and mice AChE transcripts. In humans, each of the three 5′ exons can be combined with three 3′ exons to yield nine transcripts. Similarly in mice, combination of each of five 5′ exons with three 3′ exons may form 15 transcripts. (c) The range and structural arrangement of AChE proteins. (I) Tetrameric AChES (or AChET) (orange), monomeric AChER (yellow), and dimeric AChE (or AChEH) (gray). (II) Membrane-anchored AChE variants. AChES is linked to synaptic areas with the aid of ColQ (black) in muscle and of PRiMA (blue) in brain. Membrane attachment of dimeric AChEE is mediated by a GPI moiety added to each enzyme subunit (two curved black lines). AChER remains monomeric. (III) Putative membrane docking through the extended N-terminus (N-AChE, green), which is encoded by the exon E1e of AChES (orange), AChER (yellow), or AChEE (gray)

The mRNA containing exons 4 and 5 leads to AChEH (from hydrophobic) or AChEE (from erythrocytic). In the rough endoplasmic reticulum, the AChEH subunit adds glycosylphosphatidylinositol (GPI) before dimerization and further transport to the cell surface (Fig. 2c) (Coussen et al. 2001). While GPI-linked AChEH dimers prevails in erythrocyte and lymphocytes, predominant GPI-bonded dimers coexist with some monomers in heart, liver, breast, lung, kidney, intestine, thymus, and spleen (Ruiz-Espejo et al. 2002; Gomez et al. 2003; Nieto-Ceron et al. 2005; Moral-Naranjo et al. 2010; Munoz-Delgado et al. 2010; Montenegro et al. 2014). The AChE transcript containing exons 4 and 6 produces the AChET subunit (from tailed). AChET is also called AChES (from synaptic owing to its abundance in excitable cells (neuron, glial cells, and myofibers) and tissues (brain, peripheral nerve, and muscle)). Although the AChET may occur as globular monomers and dimers in most cells and tissues, AChET polymerizes and gives globular tetramers (G4).These tetrameric assemblies exist devoid of structural tails or attached to them. In the absence of any retention tail, the AChE tetramers pass freely through the secretion pathway and provide the AChE activity measured in the blood plasma and cerebrospinal fluid. In the presence of the transmembrane tail PRiMA (proline rich membrane anchor), the tetramers are addressed to and retained in the cell membrane (Perrier et al. 2002). The synthesis in cells of PRiMA-linked tetramers needs expression of both PRIMA and ACHE genes. Insufficiency of PRiMA would affect the quantity of the cell membrane-located PRiMA-linked AChE tetramers: This deficiency would lead to overactivation of ACh receptors, and, therefore, to abnormal functioning of neural and muscular tissues (Vidal et al. 2013).

A second polypeptide to which AChE tetramers may bind consists of a triple-stranded collagen-type ColQ tail. ColQ may link one, two, or three tetramers and by this means the asymmetric A4, A8, and A12 AChE forms are built (Fig. 2c) (Massoulie 2002). Asymmetric AChE is the most abundant and physiologically relevant variant in muscle, and like PRiMA, ColQ is encoded by a separate gene, so that the making-up of asymmetric AChE requires coordinated expression of COLQ and ACHE genes. Troubles in the normal supply of ColQ protein would lead to asymmetric AChE deficiency at synaptic basal lamina, a defect which will affect normal coupling of excitation with contraction and leads to a congenital myasthenia syndrome owing to deficiency of asymmetric AChE (Karmouch et al. 2013).

Besides the 3′ splicing, the 5′ end of nonspliced AChE mRNA is also subjected to regulation, with at least five E1 exons in mouse and three exons in human. Distinct combinations of splicing at 5′ and 3′ end can produce 15 and 9 AChE mRNAs in humans and mice, respectively (Fig. 2b). The mRNAs of humans and mice including the exon E1e produce protein variants which contain an N-terminal extension. These proteins are collectively called N-AChE variants, and, in theory at least, they may exist as monomers or oligomers of N-AChER, N-AChEH, and N-AChET. It seems that a noncleaved signal peptide allows membrane anchorage and that the extra N-peptide fragment reside inside the cells (Fig. 2c III) (Meshorer et al. 2004; Meshorer and Soreq 2006).

The Physiological Roles of AChE

The best known role of AChE is the rapid inactivation of ACh after release at cholinergic synapses, ending by this means the transmission of nerve impulses, and facilitating the precise temporal control of muscle contraction (Rosenberry 1979; Taylor 1991). AChE hydrolyzes the neurotransmitter ACh in the nearby postsynaptic (or presynaptic) ACh receptors. So, it can be certainly said that AChE allows ending synaptic transmission, preventing continuous nerve firings at nerve terminals. In the neuromuscular system, the membrane depolarization-inducer ACh is destroyed instantly by junctional cleft-located and basal lamina-associated AChE. Asymmetric AChE components (A4, A8, and A12) are secreted from muscle and anchored to the basement membrane through thin stalks of collagen (Sanes and Lichtman 2001; Cohen-Cory 2002). There is evidence that AChES plays an essential role at the neuromuscular junction (Seidman et al. 1995; Harlow et al. 2001). Thus, it is widely accepted that the principal function of AChE is to perform hydrolytic deactivation of ACh.

Several congenital and acquired diseases have directly been attributed to abnormal AChE activity. Thus, a deficiency of activity in skeletal muscle leads to myophathies, whose symptoms and signs resemble those of myasthenia gravis (Sieburth et al. 2005; Engel 2007). In addition, some acquired diseases arise from a prominent loss of AChE activity. For instance, muscle disorders caused by chronic and long-lasting inhibition of AChE owing to involuntary exposure or voluntary intake of drugs or compounds, for instance pesticides, which possess potent anti-ChE activity. The list of anti-ChE agents includes: (1) organophosphosphates and carbamates, which are widely used as pesticides in greenhouses, open field crops, and grain stores for their ability to inactivate AChE of stored-product pest-inducer arthropods; (2) the nerve gases sarin and tabun, which are both stored in developed and nondeveloped countries for their eventual use as chemical weapon; and (3) the pharmacologically relevant drug pyridostigmine, which is chronically administered to patients suffering from myasthenia gravis owing to its capacity to inhibit AChE reversibly (Baker 2005; Bigalke and Rummel 2005).

At this point it is worth noting the observations regarding the unchanged AChE activity and the altered distribution of AChE components which have been seen in skeletal muscle and peripheral nerve of the Lama2dy mouse, a model of congenital muscular dystrophy (CMD) owing to deficiency of merosin (laminin-alpha2 chain) (Moral-Naranjo et al. 2002; Moral-Naranjo et al. 2010; Vidal et al. 2013).

Apart from the well-known ACh-hydrolyzing activity, a wealth of information indicates that AChE plays non hydrolytic actions. These new facets are referred to as noncatalytic functions, noncholinergic effects, or alternative actions of AChE.

Apoptosis

Among these alternative actions, apoptosis is possibly the most relevant and better understood in molecular terms. Accumulated evidence indicates that several cell types, including cells that do not form part of central and peripheral nervous systems, express AChES and the protein level increases in cells when they are subjected to apoptosis stimuli (Zhang et al. 2002). Thus, it has been observed that AChE gene silencing using antisense (AS) oligonucleotides increases both the cell number and the cell proliferation rate in primary cultures of mouse bone marrow (Jiang and Zhang 2008). Moreover, it has been reported that human lung fibroblast cells (HLF) or rat kidney cells (NRK), which in normal conditions do not express AChE, can express it when the cells enter to apoptosis (Zhang et al. 2002; Jin et al. 2004). Even more, neural cells expressing low levels of AChE, such as PC12, increase their content of AChE protein in apoptosis conditions (Yang et al. 2002; Jin et al. 2004). The above findings support a relationship between apoptosis and enhanced AChE expression, including an increase in enzyme activity, although catalytic activity has shown to be unnecessary for the regulatory actions of AChE on cell proliferation and dead (Jiang and Zhang 2008). Of note is the fact that AChE overexpression does not initiate but rather enhances the sensitivity of cells to dead stimuli (Jin et al. 2004). Park and coworkers have observed that while the use of small interfering RNA (siRNA) against AChE mRNA abolishes Apaf1-cytochrome c (cyt-c) binding, the use of siRNAs against cyt-c abrogates AChE-Apaf1 binding, and siRNA for Apaf1 fails in blocking AChE/cyt-c interaction (Park et al. 2004). These data the discovery of caveolin1-binding capacity in AChE and the finding of an ability of this binary complex to bind with cyt-c led strong support to the proposed role for AChE in apoptosome formation (Park et al. 2008).

Cell Cycle

In the last few years, the participation of AChE in cell cycle regulation has been tested. The results have shown a higher AChE level in no proliferating phase cells than in proliferating phase cells (Jiang and Zhang 2008; Xiang et al. 2008; Layer et al. 2013; Perez-Aguilar et al. 2015).

Cell proliferation and differentiation are two mutually exclusive processes so that one must be stopped to permit start the other. There is evidence that in nonneural tissues, such as bone, muscle, and hematopoietic organs, AChE increases along cell differentiation (Lev-Lehman et al. 1997; Genever et al. 1999; Serobyan et al. 2007). Since an increase in AChE might well reflect inhibition of the cell cycle, this increase might mark the switch from proliferation to differentiation. For example, when AChE is overexpressed in Caco-2 cells, an increased population of cells in the G2/M phase is observed, while the remaining cells (34%) left this phase (Xiang et al. 2008). Similarly, the cell cycle arrest observed in R28 retinal cells overexpressing AChE prompted Layer and coworker to propose AChE as a firewall to inhibit cell proliferation and support differentiation (Layer et al. 2013). Moreover, coimmunoprecipitation assays have shown binding of AChE with both Cyclin G-associated Kinase (GAK) and Aurora kinase, and amino acid sequence analysis suggests that the extra N-peptide of N-AChE possesses consensus motifs that predict protein-protein interactions between N-AChE and the cyclin-related kinases GSK3, Aurora, and GAK, besides membrane integrin receptors, and the death receptor FAS. Each of these interactions could potentially modulate N-AChES-induced apoptosis, with possible therapeutic value to alleviate Alzheimer’s disease (Toiber et al. 2009). These findings lend additional support to the proposed involvement of AChE in cell cycle arrest (antitumoral activity) by direct interaction of the enzyme with cell cycle regulatory proteins.

A high local level of ACh, arising from a low level of AChE activity, may trigger cell proliferation and apoptosis through the activation of nicotinic (nAChR) and muscarinic (mAChR) receptors (Thunnissen 2009). Thus, the AChE activity level in cells, and the ACh content in them, may contribute to the range of signal that dictate the time to start cell proliferation and/or apoptosis. In this context, it is worth mentioning the observations gathered in studies aimed to assess the impact of vagotomy on rat liver functioning. The results show that while the vagus nerve elicits the activation of hepatic progenitors through mAChR type 3, vagotomy leads to a decrease of AChE activity, so that the concurrent increase in ACh availability permits that the neurotransmitter may reach its target in oval cells to promote proliferation and liver repair (Cassiman et al. 2002). We have recently demonstrated that the inhibition of AChE activity in Huh-7 and HepG2 liver cancer cell lines increases the cell proliferation rate (Perez-Aguilar et al. 2015), a phenomenon supporting of relevant role for AChE activity in cell cycle control.

Cell Migration

The identification of AChE activity in migrating cells of sea urchin, amphibian, and chicken embryos during gastrulation events (Drews 1975) as well as in cultured mesoderm cells of Oryzias latipes (Fluck et al. 1980) gave way to the concept of AChE activity as a useful marker of migrating cells arising from the neural crest (Le Douarin 1986). In support of this is the fact that ChE inhibitors were capable of preventing spicule formation, and in so doing the inhibitors may disturb skeletal rods elongation in sea urchin (Ohta et al. 2009). The mechanism by which AChE plays this function is not known yet, but it might be related with the observation in AChE of binding sites for laminin and fibronectin (Bigbee and Sharma 2004; Anderson et al. 2008), two proteins of the extracellular matrix network. Moreover, it has been suggested that the AChE-related structural tails ColQ and PRiMA may be involved in the association of AChE with the aforementioned matrix proteins (Massoulie et al. 2008; Liang et al. 2009). Thus, there is the possibility that AChE molecules may bind directly or indirectly (via ColQ or PRiMA) with fibronectin, a protein which is especially abundant in the migration paths that cells use during morphogenesis-linked movements that occur in both invertebrate and vertebrate embryos.

AChE Involvement in Pathologies

Alzheimer’s Disease

It is widely accepted that AChE has a prominent role in Alzheimer’s disease (AD). Most researchers in the Alzheimer/cholinergic impairment relationship think that AChE may collaborate to the production of β-amyloid fibers through cholinergic and noncholinergic actions. The cholinergic hypothesis suggests that the deficiency of ACh in the hippocampus and in other memory-associated brain regions arises from a low neurotransmitter production or an increased ACh-hydrolyzing activity (Singh et al. 2013). This widely accepted cholinergic origin of AD explains the therapeutic use of AChE inhibitors for decreasing the hydrolysis of ACh and by this means slowing the development of AD (Chen et al. 2013; Yang et al. 2013; El-Malah et al. 2014). Since memory impairment is thought to be related with high AChE activity (low ACh availability), this contribution of AChE to AD corresponds to the catalytic (cholinergic) action. But AChE can also contribute to AD by means of noncatalytic actions.

Since noncholinergic effects of AChE are related to development, differentiation, and cell adhesion (Soreq and Seidman 2001), these noncatalytic functions may contribute to AD development. In this regards, it is well known that deposits of β-amyloid peptide represents a hallmark of AD pathogenesis. The fact that AChE had been identified in β-amyloid deposits suggests that AChE may contribute to AD progress (Alvarez et al. 1997; Bartolini et al. 2003). The peripheral anionic site (PAS) of AChE seems to be involved in the β-amyloid-AChE interaction, an effect apparently produced by the binding of W279 of the AChE-PAS with an electron-rich moiety of β-amyloid (Inestrosa et al. 1996; Johnson and Moore 1999; De Ferrari et al. 2001). The Inestrosa group’s reports indicate that AChE inhibitors are useful not only to prevent the loss of ACh but also to slow down the production of AChE-β-amyloid deposits. AChE inhibitors, such as propidium iodide, which bind the PAS of AChE are able to block β-amyloid aggregation, allowing progressive improvement of cognitive functions (Inestrosa et al. 1996; Munoz-Ruiz et al. 2005). The aforementioned role of AChE in apoptosis makes it possible that AChE collaborate to AD by promoting apoptosis of cholinergic neurons. In this context lies Soreq’s group results regarding the overexpression of the N-AChES variant in AD, which supports neurotoxic effects for N-AChES. Thus, in cortical brain areas of AD patients, an increased level of N-AChES has been found, which in turn matched the level of hyperphosphorylated Tau. Moreover, in cells transfected with N-AChES, the activation of GSK3, hyperphosphorylation of Tau, and increased number of cells in apoptosis are all observed (Toiber et al. 2008). So, the results suggest that an excess of N-AChES induces cell death and possibly neurodegeneration.

Cancer

There is evidence that AChE displays antitumor activity (Lu et al. 2013; Xu et al. 2014). As for tumorigenesis, aberrations in the AChE gene have been observed in cancerous tissues such as ovarian, breast, and prostate tumors, and some types of myeloid leukemia (Fischer et al. 1998; Neville et al. 2001; Bernardi et al. 2010). These gene aberrations may alter the splicing process and, therefore, the levels of AChE-R, AChE-H, and AChE-T mRNAs, the synthesis of the corresponding protein subunits, catalytic efficiency, noncatalytic actions, subunits assembly and delivery of separate oligomers to appropriate cell stores. The relationship of AChE overexpression with cell apoptosis (Zhang et al. 2002; Park et al. 2008) and cell cycle inhibition (Xiang et al. 2008; Layer et al. 2013) supports the possibility that the sharp drop in AChE activity and protein levels observed in some types of cancers (Vidal 2005) may lead to apoptosis arrest (enhanced survival), and, possibly, to cell growth and proliferation, which may expand the number of tumor cells or increase the tumor aggressiveness.

A decrease of AChE activity has been observed in a variety of cancerous tissues, such as lung tumors (Martinez-Lopez et al. 2008), head and neck carcinomas, which arise from the mucosal lining of the digestive tract (Castillo-Gonzalez et al. 2015a), laryngeal cancer (Castillo-Gonzalez et al. 2015b), colon carcinoma (Montenegro et al. 2006), and liver tumors (Zhao et al. 2011; Perez-Aguilar et al. 2015). The decreased AChE expression in cancerous specimens suggests that the protein may collaborate to the development and/or maintenance of tumors. As mentioned earlier, through interaction with nAChR and mAChR, ACh is able to induce cell proliferation and apoptosis arrest. The decline in AChE activity would increase the local level of ACh, and, if the increase persists in time, the cholinergic signal may cause long-lasting effects. In this regard, it is worth mentioning the ACh-forming capacity that exhibit both liver carcinoma cells and hepatocarcinoma cell lines (Wang et al. 2008; Zhao et al. 2011). Still more, and as it might be expected, an inverse relationship was observed between the level of ACh in liver carcinoma cells and the level of AChE activity in them (Zhao et al. 2011; Xu et al. 2014). The same inverse ratio has been reported to exist in small cell lung carcinoma (Song et al. 2003). The drop of AChE and the increased ACh availability, which is particularly relevant in tumors, may causally be related with tumor progression (Perez-Aguilar et al. 2015).

Notes

Acknowledgments

The work was supported by grants of the CONACYT 252942, 2015-02-1320, SEP-PRODEP-913026-1461211, and Universidad Autónoma Metropolitana Iztapalapa.

References

  1. Alvarez A, Opazo C, Alarcon R, Garrido J, Inestrosa NC. Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils. J Mol Biol. 1997;272:348–61. doi: 10.1006/jmbi.1997.1245.CrossRefPubMedGoogle Scholar
  2. Anderson AA, Ushakov DS, Ferenczi MA, Mori R, Martin P, Saffell JL. Morphoregulation by acetylcholinesterase in fibroblasts and astrocytes. J Cell Physiol. 2008;215:82–100. doi: 10.1002/jcp.21288.CrossRefPubMedGoogle Scholar
  3. Ariel N, Ordentlich A, Barak D, Bino T, Velan B, Shafferman A. The “aromatic patch” of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors. Biochem J. 1998;335(Pt 1):95–102.PubMedCentralCrossRefPubMedGoogle Scholar
  4. Augustinsson KB, Nachmansohn D. Distinction between acetylcholine-esterase and other choline ester-splitting enzymes. Science. 1949;110:98–9. doi: 10.1126/science.110.2847.98.CrossRefPubMedGoogle Scholar
  5. Baker DJ. Critical care requirements after mass toxic agent release. Crit Care Med. 2005;33:S66–74.CrossRefPubMedGoogle Scholar
  6. Bartolini M, Bertucci C, Cavrini V, Andrisano V. Beta-amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol. 2003;65:407–16.CrossRefPubMedGoogle Scholar
  7. Bernardi CC, Ribeiro Ede S, Cavalli IJ, Chautard-Freire-Maia EA, Souza RL. Amplification and deletion of the ACHE and BCHE cholinesterase genes in sporadic breast cancer. Cancer Genet Cytogenet. 2010;197:158–65. doi: 10.1016/j.cancergencyto.2009.10.011.CrossRefPubMedGoogle Scholar
  8. Bigalke H, Rummel A. Medical aspects of toxin weapons. Toxicology. 2005;214:210–20. doi: 10.1016/j.tox.2005.06.015.CrossRefPubMedGoogle Scholar
  9. Bigbee JW, Sharma KV. The adhesive role of acetylcholinesterase (AChE): detection of AChE binding proteins in developing rat spinal cord. Neurochem Res. 2004;29:2043–50.CrossRefPubMedGoogle Scholar
  10. Brown GL, Dale HH, Feldberg W. Reactions of the normal mammalian muscle to acetylcholine and to eserine. J Physiol. 1936;87:394–424.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Cassiman D, Libbrecht L, Sinelli N, Desmet V, Denef C, Roskams T. The vagal nerve stimulates activation of the hepatic progenitor cell compartment via muscarinic acetylcholine receptor type 3. Am J Pathol. 2002;161:521–30. doi: 10.1016/S0002-9440(10)64208-3.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Castillo-Gonzalez AC, Nieto-Ceron S, Pelegrin-Hernandez JP, Montenegro MF, Noguera JA, Lopez-Moreno MF, et al. Dysregulated cholinergic network as a novel biomarker of poor prognostic in patients with head and neck squamous cell carcinoma. BMC Cancer. 2015a;15:385. doi: 10.1186/s12885-015-1402-y.PubMedCentralCrossRefPubMedGoogle Scholar
  13. Castillo-Gonzalez AC, Pelegrin-Hernandez JP, Nieto-Ceron S, Madrona AP, Noguera JA, Lopez-Moreno MF, et al. Unbalanced acetylcholinesterase activity in larynx squamous cell carcinoma. Int Immunopharmacol. 2015b;29:81–6. doi: 10.1016/j.intimp.2015.05.011.CrossRefPubMedGoogle Scholar
  14. Cohen-Cory S. The developing synapse: construction and modulation of synaptic structures and circuits. Science. 2002;298:770–6. doi: 10.1126/science.1075510.CrossRefPubMedGoogle Scholar
  15. Coussen F, Ayon A, Le Goff A, Leroy J, Massoulie J, Bon S. Addition of a glycophosphatidylinositol to acetylcholinesterase. Processing, degradation, and secretion. J Biol Chem. 2001;276:27881–92. doi: 10.1074/jbc.M010817200.CrossRefPubMedGoogle Scholar
  16. Chen Y, Sun J, Peng S, Liao H, Zhang Y, Lehmann J. Tacrine-flurbiprofen hybrids as multifunctional drug candidates for the treatment of Alzheimer’s disease. Arch Pharm. 2013;346:865–71. doi: 10.1002/ardp.201300074.CrossRefGoogle Scholar
  17. Dale HH. The action of certain esters and ethers of choline, and their relation to muscarine. J Pharmacol Exp Ther. 1914;6:147–90.Google Scholar
  18. De Ferrari GV, Canales MA, Shin I, Weiner LM, Silman I, Inestrosa NC. A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry. 2001;40:10447–57.CrossRefPubMedGoogle Scholar
  19. de Martinez-Lopez CA, Nieto-Ceron S, Aurelio PC, Galbis-Martinez L, Latour-Perez J, Torres-Lanzas J, et al. Cancer-associated differences in acetylcholinesterase activity in bronchial aspirates from patients with lung cancer. Clin Sci. 2008;115:245–53. doi: 10.1042/CS20070393.CrossRefGoogle Scholar
  20. Drews U. Cholinesterase in embryonic development. Prog Histochem Cytochem. 1975;7:1–52.CrossRefPubMedGoogle Scholar
  21. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL. Acetylcholinesterase: from 3D structure to function. Chem Biol Interact. 2010;187:10–22. doi: 10.1016/j.cbi.2010.01.042.PubMedCentralCrossRefPubMedGoogle Scholar
  22. El-Malah A, Gedawy EM, Kassab AE, Salam RM. Novel tacrine analogs as potential cholinesterase inhibitors in Alzheimer’s disease. Arch Pharm. 2014;347:96–103. doi: 10.1002/ardp.201300121.CrossRefGoogle Scholar
  23. Engel AG. The therapy of congenital myasthenic syndromes. Neurotherapeutics. 2007;4:252–7. doi: 10.1016/j.nurt.2007.01.001.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Fischer K, Brown J, Scherer SW, Schramm P, Stewart J, Fugazza G, et al. Delineation of genomic regions in chromosome band 7q22 commonly deleted in myeloid leukemias. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 1998;144:46–52.PubMedGoogle Scholar
  25. Fluck RA, Wynshaw-Boris AJ, Schneider LM. Cholinergic molecules modify the in vitro behavior of cells from early embryos of the medaka Oryzias latipes, a teleost fish. Comp Biochem Physiol C. 1980;67C:29–34.CrossRefPubMedGoogle Scholar
  26. Genever PG, Birch MA, Brown E, Skerry TM. Osteoblast-derived acetylcholinesterase: a novel mediator of cell-matrix interactions in bone? Bone. 1999;24:297–303.CrossRefPubMedGoogle Scholar
  27. Getman DK, Eubanks JH, Camp S, Evans GA, Taylor P. The human gene encoding acetylcholinesterase is located on the long arm of chromosome 7. Am J Hum Genet. 1992;51:170–7.PubMedCentralPubMedGoogle Scholar
  28. Gomez JL, Nieto-Ceron S, Campoy FJ, Munoz-Delgado E, Vidal CJ. Purification and properties of hydrophilic dimers of acetylcholinesterase from mouse erythrocytes. Int J Biochem Cell Biol. 2003;35:1109–18.CrossRefPubMedGoogle Scholar
  29. Harlow ML, Ress D, Stoschek A, Marshall RM, McMahan UJ. The architecture of active zone material at the frog’s neuromuscular junction. Nature. 2001;409:479–84. doi: 10.1038/35054000.CrossRefPubMedGoogle Scholar
  30. Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C, et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron. 1996;16:881–91.CrossRefPubMedGoogle Scholar
  31. Jiang H, Zhang XJ. Acetylcholinesterase and apoptosis. A novel perspective for an old enzyme. FEBS J. 2008;275:612–7. doi: 10.1111/j.1742-4658.2007.06236.x.CrossRefPubMedGoogle Scholar
  32. Jin QH, He HY, Shi YF, Lu H, Zhang XJ. Overexpression of acetylcholinesterase inhibited cell proliferation and promoted apoptosis in NRK cells. Acta Pharmacol Sin. 2004;25:1013–21.PubMedGoogle Scholar
  33. Johnson G, Moore SW. The adhesion function on acetylcholinesterase is located at the peripheral anionic site. Biochem Biophys Res Commun. 1999;258:758–62. doi: 10.1006/bbrc.1999.0705.CrossRefPubMedGoogle Scholar
  34. Karmouch J, Dobbertin A, Sigoillot S, Legay C. Developmental consequences of the ColQ/MuSK interactions. Chem Biol Interact. 2013;203(1):287–291. doi: 10.1016/j.cbi.2012.10.006.
  35. Katz B. Nerve, muscle, and synapse. New York: McGraw-Hill; 1966.Google Scholar
  36. Kaufer D, Friedman A, Seidman S, Soreq H. Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature. 1998;393:373–7. doi: 10.1038/30741.CrossRefPubMedGoogle Scholar
  37. Layer PG, Klaczinski J, Salfelder A, Sperling LE, Thangaraj G, Tuschl C, et al. Cholinesterases in development: AChE as a firewall to inhibit cell proliferation and support differentiation. Chem Biol Interact. 2013;203:269–76. doi: 10.1016/j.cbi.2012.09.014.CrossRefPubMedGoogle Scholar
  38. Le Douarin NM. Investigations on the neural crest. Methodological aspects and recent advances. Ann N Y Acad Sci. 1986;486:66–86.CrossRefPubMedGoogle Scholar
  39. Legay C. Why so many forms of acetylcholinesterase? Microsc Res Tech. 2000;49:56–72. doi: 10.1002/(SICI)1097-0029(20000401)49:1<56::AID-JEMT7>3.0.CO;2-R.CrossRefPubMedGoogle Scholar
  40. Lev-Lehman E, Deutsch V, Eldor A, Soreq H. Immature human megakaryocytes produce nuclear-associated acetylcholinesterase. Blood. 1997;89:3644–53.PubMedGoogle Scholar
  41. Liang D, Blouet JP, Borrega F, Bon S, Massoulie J. Respective roles of the catalytic domains and C-terminal tail peptides in the oligomerization and secretory trafficking of human acetylcholinesterase and butyrylcholinesterase. FEBS J. 2009;276:94–108. doi: 10.1111/j.1742-4658.2008.06756.x.CrossRefPubMedGoogle Scholar
  42. Lu L, Zhang X, Zhang B, Wu J, Zhang X. Synaptic acetylcholinesterase targeted by microRNA-212 functions as a tumor suppressor in non-small cell lung cancer. Int J Biochem Cell Biol. 2013;45:2530–40. doi: 10.1016/j.biocel.2013.08.007.CrossRefPubMedGoogle Scholar
  43. Massoulie J. The origin of the molecular diversity and functional anchoring of cholinesterases. Neurosignals. 2002;11:130–43. doi:65054CrossRefPubMedGoogle Scholar
  44. Massoulie J, Perrier N, Noureddine H, Liang D, Bon S. Old and new questions about cholinesterases. Chem Biol Interact. 2008;175:30–44. doi: 10.1016/j.cbi.2008.04.039.CrossRefPubMedGoogle Scholar
  45. Massoulie J, Pezzementi L, Bon S, Krejci E, Vallette FM. Molecular and cellular biology of cholinesterases. Prog Neurobiol. 1993;41:31–91.CrossRefPubMedGoogle Scholar
  46. Meshorer E, Erb C, Gazit R, Pavlovsky L, Kaufer D, Friedman A, et al. Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity. Science. 2002;295:508–12. doi: 10.1126/science.1066752.CrossRefPubMedGoogle Scholar
  47. Meshorer E, Soreq H. Virtues and woes of AChE alternative splicing in stress-related neuropathologies. Trends Neurosci. 2006;29:216–24. doi: 10.1016/j.tins.2006.02.005.CrossRefPubMedGoogle Scholar
  48. Meshorer E, Toiber D, Zurel D, Sahly I, Dori A, Cagnano E, et al. Combinatorial complexity of 5′ alternative acetylcholinesterase transcripts and protein products. J Biol Chem. 2004;279:29740–51. doi: 10.1074/jbc.M402752200.CrossRefPubMedGoogle Scholar
  49. Montenegro MF, Nieto-Ceron S, Cabezas-Herrera J, Munoz-Delgado E, Campoy FJ, Vidal CJ. Most acetylcholinesterase activity of non-nervous tissues and cells arises from the AChE-H transcript. J Mol Neurosci. 2014;53:429–35. doi: 10.1007/s12031-013-0172-8.CrossRefPubMedGoogle Scholar
  50. Montenegro MF, Ruiz-Espejo F, Campoy FJ, Munoz-Delgado E, de la Cadena MP, Rodriguez-Berrocal FJ, et al. Cholinesterases are down-expressed in human colorectal carcinoma. Cell Mol Life Sci. 2006;63:2175–82. doi: 10.1007/s00018-006-6231-3.CrossRefPubMedGoogle Scholar
  51. Moral-Naranjo MT, Cabezas-Herrera J, Vidal CJ, Campoy FJ. Muscular dystrophy with laminin deficiency decreases the content of butyrylcholinesterase tetramers in sciatic nerves of Lama2dy mice. Neurosci Lett. 2002;331:155–8.CrossRefPubMedGoogle Scholar
  52. Moral-Naranjo MT, Montenegro MF, Munoz-Delgado E, Campoy FJ, Vidal CJ. The levels of both lipid rafts and raft-located acetylcholinesterase dimers increase in muscle of mice with muscular dystrophy by merosin deficiency. Biochim Biophys Acta. 2010;1802:754–64. doi: 10.1016/j.bbadis.2010.05.011.CrossRefPubMedGoogle Scholar
  53. Munoz-Delgado E, Montenegro MF, Campoy FJ, Moral-Naranjo MT, Cabezas-Herrera J, Kovacs G, et al. Expression of cholinesterases in human kidney and its variation in renal cell carcinoma types. FEBS J. 2010;277:4519–29. doi: 10.1111/j.1742-4658.2010.07861.x.CrossRefPubMedGoogle Scholar
  54. Munoz-Ruiz P, Rubio L, Garcia-Palomero E, Dorronsoro I, del Monte-Millan M, Valenzuela R, et al. Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer’s disease. J Med Chem. 2005;48:7223–33. doi: 10.1021/jm0503289.CrossRefPubMedGoogle Scholar
  55. Nachmansohn D, Neumann E. Chemical and molecular basis of nerve activity. New York: Academic Press; 1975.Google Scholar
  56. Nachmansohn D, Wilson IB. The enzymic hydrolysis and synthesis of acetylcholine. Adv Enzymol Relat Subj Biochem. 1951;12:259–339.PubMedGoogle Scholar
  57. Neville PJ, Thomas N, Campbell IG. Loss of heterozygosity at 7q22 and mutation analysis of the CDP gene in human epithelial ovarian tumors. Int J Cancer. 2001;91:345–9.CrossRefPubMedGoogle Scholar
  58. Nieto-Ceron S, del Campo LF, Munoz-Delgado E, Vidal CJ, Campoy FJ. Muscular dystrophy by merosin deficiency decreases acetylcholinesterase activity in thymus of Lama2dy mice. J Neurochem. 2005;95:1035–46. doi: 10.1111/j.1471-4159.2005.03433.x.CrossRefPubMedGoogle Scholar
  59. Ohta K, Takahashi C, Tosuji H. Inhibition of spicule elongation in sea urchin embryos by the acetylcholinesterase inhibitor eserine. Comp Biochem Physiol B Biochem Mol Biol. 2009;153:310–6. doi: 10.1016/j.cbpb.2009.04.001.CrossRefPubMedGoogle Scholar
  60. Ordentlich A, Barak D, Kronman C, Ariel N, Segall Y, Velan B, et al. Contribution of aromatic moieties of tyrosine 133 and of the anionic subsite tryptophan 86 to catalytic efficiency and allosteric modulation of acetylcholinesterase. J Biol Chem. 1995;270:2082–91.CrossRefPubMedGoogle Scholar
  61. Ordentlich A, Barak D, Kronman C, Flashner Y, Leitner M, Segall Y, et al. Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Identification of residues constituting the anionic site, the hydrophobic site, and the acyl pocket. J Biol Chem. 1993;268:17083–95.PubMedGoogle Scholar
  62. Park SE, Jeong SH, Yee SB, Kim TH, Soung YH, Ha NC, et al. Interactions of acetylcholinesterase with caveolin-1 and subsequently with cytochrome c are required for apoptosome formation. Carcinogenesis. 2008;29:729–37. doi: 10.1093/carcin/bgn036.CrossRefPubMedGoogle Scholar
  63. Park SE, Kim ND, Yoo YH. Acetylcholinesterase plays a pivotal role in apoptosome formation. Cancer Res. 2004;64:2652–5.CrossRefPubMedGoogle Scholar
  64. Perez-Aguilar B, Vidal CJ, Palomec G, Garcia-Dolores F, Gutierrez-Ruiz MC, Bucio L, et al. Acetylcholinesterase is associated with a decrease in cell proliferation of hepatocellular carcinoma cells. Biochim Biophys Acta. 2015;1852:1380–7. doi: 10.1016/j.bbadis.2015.04.003.CrossRefPubMedGoogle Scholar
  65. Perrier AL, Massoulie J, Krejci E. PRiMA: the membrane anchor of acetylcholinesterase in the brain. Neuron. 2002;33:275–85.CrossRefPubMedGoogle Scholar
  66. Pohanka M. Cholinesterases, a target of pharmacology and toxicology. Biomed Pap Med Fac Univ Palacky Olomouc Czech. 2011;155:219–29. doi: 10.5507/bp.2011.036.CrossRefGoogle Scholar
  67. Quinn DM. Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states. Chem Rev. 1987;87:955–79. doi: 10.1021/cr00081a005.CrossRefGoogle Scholar
  68. Radic Z, Gibney G, Kawamoto S, MacPhee-Quigley K, Bongiorno C, Taylor P. Expression of recombinant acetylcholinesterase in a baculovirus system: kinetic properties of glutamate 199 mutants. Biochemistry. 1992;31:9760–7.CrossRefPubMedGoogle Scholar
  69. Rosenberry TL. Quantitative simulation of endplate currents at neuromuscular junctions based on the reaction of acetylcholine with acetylcholine receptor and acetylcholinesterase. Biophys J. 1979;26:263–89. doi: 10.1016/S0006-3495(79)85249-2.PubMedCentralCrossRefPubMedGoogle Scholar
  70. Ruiz-Espejo F, Cabezas-Herrera J, Illana J, Campoy FJ, Vidal CJ. Cholinesterase activity and acetylcholinesterase glycosylation are altered in human breast cancer. Breast Cancer Res Treat. 2002;72:11–22.CrossRefPubMedGoogle Scholar
  71. Sanes JR, Lichtman JW. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci. 2001;2:791–805. doi: 10.1038/35097557.CrossRefPubMedGoogle Scholar
  72. Schwarz M, Glick D, Loewenstein Y, Soreq H. Engineering of human cholinesterases explains and predicts diverse consequences of administration of various drugs and poisons. Pharmacol Ther. 1995;67:283–322.CrossRefPubMedGoogle Scholar
  73. Seidman S, Sternfeld M, Ben Aziz-Aloya R, Timberg R, Kaufer-Nachum D, Soreq H. Synaptic and epidermal accumulations of human acetylcholinesterase are encoded by alternative 3′-terminal exons. Mol Cell Biol. 1995;15:2993–3002.PubMedCentralCrossRefPubMedGoogle Scholar
  74. Serobyan N, Jagannathan S, Orlovskaya I, Schraufstatter I, Skok M, Loring J, et al. The cholinergic system is involved in regulation of the development of the hematopoietic system. Life Sci. 2007;80:2352–60. doi: 10.1016/j.lfs.2007.04.017.PubMedCentralCrossRefPubMedGoogle Scholar
  75. Sieburth D, Ch’ng Q, Dybbs M, Tavazoie M, Kennedy S, Wang D, et al. Systematic analysis of genes required for synapse structure and function. Nature. 2005;436:510–7. doi: 10.1038/nature03809.CrossRefPubMedGoogle Scholar
  76. Singh M, Kaur M, Kukreja H, Chugh R, Silakari O, Singh D. Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. Eur J Med Chem. 2013;70:165–88. doi: 10.1016/j.ejmech.2013.09.050.CrossRefPubMedGoogle Scholar
  77. Song P, Sekhon HS, Jia Y, Keller JA, Blusztajn JK, Mark GP, et al. Acetylcholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma. Cancer Res. 2003;63:214–21.PubMedGoogle Scholar
  78. Soreq H, Seidman S. Acetylcholinesterase–new roles for an old actor. Nat Rev Neurosci. 2001;2:294–302. doi: 10.1038/35067589.CrossRefPubMedGoogle Scholar
  79. Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, et al. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science. 1991;253:872–9.CrossRefPubMedGoogle Scholar
  80. Sussman JL, Harel M, Silman I. Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs. Chem Biol Interact. 1993;87:187–97.CrossRefPubMedGoogle Scholar
  81. Taylor P. The cholinesterases. J Biol Chem. 1991;266:4025–8.PubMedGoogle Scholar
  82. Taylor P, Lappi S. Interaction of fluorescence probes with acetylcholinesterase. The site and specificity of propidium binding. Biochemistry. 1975;14:1989–97.CrossRefPubMedGoogle Scholar
  83. Taylor P, Radic Z. The cholinesterases: from genes to proteins. Annu Rev Pharmacol Toxicol. 1994;34:281–320. doi: 10.1146/annurev.pa.34.040194.001433.CrossRefPubMedGoogle Scholar
  84. Thunnissen FB. Acetylcholine receptor pathway and lung cancer. J Thorac Oncol. 2009;4:943–6. doi: 10.1097/JTO.0b013e3181ad83fc.CrossRefPubMedGoogle Scholar
  85. Toiber D, Berson A, Greenberg D, Melamed-Book N, Diamant S, Soreq H. N-acetylcholinesterase-induced apoptosis in Alzheimer’s disease. PLoS One. 2008;3:e3108. doi: 10.1371/journal.pone.0003108.PubMedCentralCrossRefPubMedGoogle Scholar
  86. Toiber D, Greenberg DS, Soreq H. Pro-apoptotic protein-protein interactions of the extended N-AChE terminus. J Neural Transm. 2009;116:1435–42. doi: 10.1007/s00702-009-0249-2.PubMedCentralCrossRefPubMedGoogle Scholar
  87. Vidal CJ. Expression of cholinesterases in brain and non-brain tumours. Chem Biol Interact. 2005;157–158:227–32. doi: 10.1016/j.cbi.2005.10.035.CrossRefPubMedGoogle Scholar
  88. Vidal CJ, Montenegro MF, Munoz-Delgado E, Campoy FJ, Cabezas-Herrera J, Moral-Naranjo MT. The AChE membrane-binding tail PRiMA is down-regulated in muscle and nerve of mice with muscular dystrophy by merosin deficiency. Chem Biol Interact. 2013;203:330–4. doi: 10.1016/j.cbi.2012.08.001.CrossRefPubMedGoogle Scholar
  89. Wang Y, Wang T, Shi X, Wan D, Zhang P, He X, et al. Analysis of acetylcholine, choline and butyrobetaine in human liver tissues by hydrophilic interaction liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 2008;47:870–5. doi: 10.1016/j.jpba.2008.02.022.CrossRefPubMedGoogle Scholar
  90. Xiang AC, Xie J, Zhang XJ. Acetylcholinesterase in intestinal cell differentiation involves G2/M cell cycle arrest. Cell Mol Life Sci. 2008;65:1768–79. doi: 10.1007/s00018-008-8016-3.CrossRefPubMedGoogle Scholar
  91. Xu H, Shen Z, Xiao J, Yang Y, Huang W, Zhou Z, et al. Acetylcholinesterase overexpression mediated by oncolytic adenovirus exhibited potent anti-tumor effect. BMC Cancer. 2014;14:668. doi: 10.1186/1471-2407-14-668.PubMedCentralCrossRefPubMedGoogle Scholar
  92. Yang L, He HY, Zhang XJ. Increased expression of intranuclear AChE involved in apoptosis of SK-N-SH cells. Neurosci Res. 2002;42:261–8.CrossRefPubMedGoogle Scholar
  93. Yang WN, Han H, Hu XD, Feng GF, Qian YH. The effects of perindopril on cognitive impairment induced by d-galactose and aluminum trichloride via inhibition of acetylcholinesterase activity and oxidative stress. Pharmacol Biochem Behav. 2013;114–115:31–6. doi: 10.1016/j.pbb.2013.10.027.CrossRefPubMedGoogle Scholar
  94. Zhang XJ, Yang L, Zhao Q, Caen JP, He HY, Jin QH, et al. Induction of acetylcholinesterase expression during apoptosis in various cell types. Cell Death Differ. 2002;9:790–800. doi: 10.1038/sj.cdd.4401034.CrossRefPubMedGoogle Scholar
  95. Zhao Y, Wang X, Wang T, Hu X, Hui X, Yan M, et al. Acetylcholinesterase, a key prognostic predictor for hepatocellular carcinoma, suppresses cell growth and induces chemosensitization. Hepatology. 2011;53:493–503. doi: 10.1002/hep.24079.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Benjamín Pérez-Aguilar
    • 1
  • Cecilio J. Vidal
    • 2
  • José Luis Gomez-Olivares
    • 1
  • Monserrat Gerardo-Ramirez
    • 1
  • Ma. Concepción Gutiérrez-Ruiz
    • 1
  • Luis E. Gomez-Quiroz
    • 1
  1. 1.Departamento de Ciencias de la SaludUniversidad Autónoma Metropolitana-IztapalapaMéxico DFMéxico
  2. 2.Departamento de Bioquímica y Biología Molecular-AUniversidad de Murcia, IMIB-Arrixaca, Regional Campus of International Excellence “Campus Mare Nostrum”MurciaSpain