acetylcholinesterase and apoptosis : a novel perspective for an old enzyme

MINIREVIEW

Acetylcholinesterase and apoptosis

A novel perspective for an old enzyme

Hua Jiang and Xue-Jun Zhang

Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, China

Acetylcholinesterase is recognized as being actively

involved in cholinergic neurotransmission. In addition,

levels of this enzyme vary gradually during differentia-

tion, apoptosis and the genesis of neurodegenerative

diseases [1,2]. These processes are correlated with the

control of cell growth, including both cell proliferation

and cell death. In mammals, acetylcholinesterase is

encoded by a single gene, ACHE, but, because of alter-

native splicing at the C-terminus of acetylcholinester-

ase mRNA, it has three different isoforms: synaptic (S)

or tail (T), erythrocytic (E) and read-through (R) [3].

These acetylcholinesterase variants selectively partici-

pate in the processes involved in promoting or attenu-

ating cell death that accompany changes in expression,

distribution and balance among the enzyme variants.

In this minireview, we discuss recent progress in

studying the role of acetylcholinesterase in the control

of cell growth and suggest the possible underlying

molecular basis from a non-classical view.

Evidence regarding the involvement ofacetylcholinesterase in apoptosis

Indirect evidence that acetylcholinesterase is involved

in regulating cell proliferation and apoptosis is derived

from studies in which certain cell-differentiation mod-

els were treated with antisense (AS) oligonuleotides

corresponding to the ACHE or BCHE gene. Inhibition

of acetylcholinesterase gene expression using this

method increased the cell count and enhanced cell

proliferation in mouse bone marrow primary cul-

tures. Furthermore, AS-acetylcholinesterase suppres-

sed apoptosis-associated DNA fragmentation in

progeny cells originating from the differentiation of

Keywords

acetylcholinesterase; alternative splicing;

apoptosis; catalytic activity; isoform;

peptide; proliferation; protein distribution;

protein partners; transcription

Correspondence

X.-J. Zhang, Laboratory of Molecular Cell

Biology, Institute of Biochemistry and Cell

Biology, Shanghai Institutes for Biological

Sciences, Chinese Academy of Sciences,

320 YueYang Road, Shanghai 200031, China

Fax: +86 21 5492 1403

Tel: +86 21 5492 1402

E-mail: [email protected]

(Received 17 August 2007, accepted

29 November 2007)

doi:10.1111/j.1742-4658.2007.06236.x

Acetylcholinesterase is indispensable for terminating acetylcholine-mediated

neurotransmission at cholinergic synapses. In addition, there is evidence to

suggest that acetylcholinesterase contributes to various physiological pro-

cesses through its involvement in the regulation of cell proliferation, differ-

entiation and survival. The effects of acetylcholinesterase depend on the

cell type and cell-differentiation state, the modulation of expression levels,

cellular distribution and binding with its protein partners. This minireview

highlights recent progress that has advanced our understanding of the role

of acetylcholinesterase in the process of cell proliferation and apoptosis.

Abbreviations

AChE-R, acetylcholinesterase R-isoform; AChE-S, acetylcholinesterase S-isoform; AS, antisense; CBF, CCAAT binding factor; JNK, c-Jun

N-terminal kinase; N-AChE-R, acetylcholinesterase R-isoform with extended N-terminus; PKC, protein kinase C.

612 FEBS Journal 275 (2008) 612–617 ª 2008 The Authors Journal compilation ª 2008 FEBS

hematopoietic stem cells [4]. The functions of cholines-

terase during tissue differentiation were investigated by

cloning a fragment of the BCHE gene in the AS orien-

tation and transfecting it into retinal cells isolated

from chick embryos. Although this did not identify the

apoptotic functions and isoform types of acetylcholin-

esterase, increased apoptosis was observed, accompa-

nied by suppressed butyrylcholinesterase expression

and enhanced acetylcholinesterase expression in AS-

butyrylcholinesterase-treated cells [5]. More direct

evidence that acetylcholinesterase contributed to the

loss of retinal function was obtained by assessing

acetylcholinesterase in retinal photoreceptors following

light-induced damage. Although formation of the inner

retina network was completely eliminated in newborn

acetylcholinesterase-knockout mice, a novel acetylcho-

linesterase variant in which the acetylcholinesterase

R-isoform (AChE-R) has an extended N-terminus

(N-AChE-R) exacerbated photic stress-induced death

of adult photoreceptors. The orphan AS agent

minimized N-AChE-R expression and facilitated the

recovery of retinal functions [6,7]. Thus, proteins

encoded by the ACHE gene have a role in modulating

tissue formation or cell death.

In addition to reports in in vivo systems, we used

cultured cells, which can be regarded as a relatively

explicit system, and treated them with variable apopto-

tic stimuli. We observed that the S variant of acetyl-

cholinesterase (AChE-S) emerged in almost all the

apoptotic cells of different tissue origin [8]. In PC12

cells, expression of AChE-S but not AChE-R was

enhanced in response to apoptosis initiated by calcium

influx [9]. Unlike AChE-S or N-AChE-R, AChE-R

was suggested to play a role in the body’s response to

acute stress and prevention of further injury. Thus,

AChE-R, but not AChE-S, transgenic mice display

more resistance to age-dependent neurodegeneration

[10]. Furthermore, AChE-R, and the C-terminal pep-

tide cleaved from it, exerted proliferative effects on

blood cells [11,12]. Although the molecular cascades

underlying the reciprocal effects among different

acetylcholinesterase variants have not been fully eluci-

dated, these cumulative, multisite observations demon-

strate that acetylcholinesterase plays a complex role in

modulating cell growth and death.

Regulation of acetylcholinesteraseexpression in apoptosis

The expression of acetylcholinesterase variants depends

on both stress-induced promoter activation and post-

transcriptional modulation, including mRNA stability,

alternative mRNA splicing, translational control and

protein modification. There is evidence regarding the

correlation between the stress-activated protein kinase

family and apoptosis-associated acetylcholinesterase

expression. Phosphorylation of c-Jun N-terminal kinas-

es (JNK) and their downstream transcription factor,

c-Jun, was enhanced during apoptosis induced by the

DNA topoisomerase inhibitors etoposide or excisa-

nin A. A corresponding increase in acetylcholinesterase

expression in the apoptotic cells was observed. This

upregulation in acetylcholinesterase was eliminated by

administering a JNK inhibitor, silencing JNK with

siRNA or antagonizing c-Jun with a dominant-nega-

tive c-Jun mutant [13].

The acetylcholinesterase promoter is also sensitive to

signals initiated by alterations in intracellular

Ca2+ levels. Mobilizing intracellular Ca2+ enhanced

acetylcholinesterase mRNA stability and, thereafter,

activation of the acetylcholinesterase promoter; how-

ever, the mechanism contributing to this enhanced sta-

bility during apoptosis remains unclear. One possible

mechanism may involve the calcium-mediated RNA-

binding protein [14]. It has been shown that acetylcho-

linesterase promoter activation targets several sites on

the acetylcholinesterase promoter. The CCAAT motif

was identified and binds the CCAAT binding factor

(CBF ⁄NF-Y); this had a suppressive effect on acetyl-

cholinesterase promoter activity [15]. Increased intra-

cellular Ca2+ levels would enable CBF ⁄NF-Y release

from this motif and therefore promoted activation of

the promoter [16], but factors modulating CBF ⁄NF-Y

and CCAAT binding in response to altered calcium

signals are unknown. Because of a redundancy in

Ca2+ signal transduction during apoptosis, acetylcho-

linesterase promoter activation is also mediated by two

calcium-dependent proteins, namely calpain and calci-

neurin. The signal cascade among calpain, calcineurin,

and nuclear factor of activated T cells (NFAT) is sup-

posedly involved in the final stages of acetylcholines-

terase promoter activation [17]. Further investigation

uncovered a more complex GSK-3b involved modulat-

ing mechanism in AChE level in apoptotic PC12 cells.

The increased intracellular Ca2+ levels induced the

GSK-3b activation and a parallel upregulation in

mRNA and protein levels of AChE-S and AChE-R

variants in apoptotic PC12 cells. Although the rela-

tionship between AChE variants and GSK-3b remain

to be elucidated, the increase in AChE-S but not

AChE-R variant was blocked by GSK-3b inhibitor.

Considering the GSK-3b is contributed to apoptosis,

thus these results suggested the dissimilar functions of

the AChE variants [9].

Little is known about the mechanisms underlying

the selective splicing choices between AChE-S and

H. Jiang and X.-J. Zhang Acetylcholinesterase and apoptosis

FEBS Journal 275 (2008) 612–617 ª 2008 The Authors Journal compilation ª 2008 FEBS 613

AChE-R. Undoubtedly, the balance between the two

acetylcholinesterase variants is critical for functional

outcome. A shift from AChE-S to AChE-R was obser-

ved during promegakaryotic cell differentiation in res-

ponse to alterations in the level of intracellular Ca2+. It

is hypothesized that the microRNA levels modulate the

shift of mRNA variant types from AChE-S to AChE-R

through acetylcholinesterase, protein kinase C (PKC),

and protein kinase A cascades. This shift enhanced cell

differentiation and suppression of cell death [18], and

was also evident in the Alzheimer’s disease brain [19].

In the stress-induced shift from the AChE-S to AChE-R

mRNA variant, the SC35 splicing factor was involved

in a reciprocal reinforcing manner [20].

Alternative acetylcholinesterasedistributions and apoptosis

It is still not known whether the cellular distribution

pattern of acetylcholinesterase is the primary basis for

the apoptotic functions of this enzyme. However, spe-

cific acetylcholinesterase variants and distributions have

been observed in apoptotic cells. We observed that the

expression of AChE-S was markedly increased in the

perinuclear and nuclear regions of apoptotic cells. Dur-

ing the late stages of apoptosis, acetylcholinesterase

accumulates inside the apoptotic body with condensed

chromatin [8,21]. The perinuclear distribution of acetyl-

cholinesterase implies that it is located in the endo-

plasmic reticulum; an implication that was confirmed

by co-localization of acetylcholinesterase and calnexin,

an endoplasmic reticulum marker protein (data not

shown). This distribution pattern is consistent with that

of acetylcholinesterase in non-neuronal cells [22]. Dur-

ing apoptosis, AChE-S is synthesized and probably

retained in the endoplasmic reticulum and awaits trans-

portation to nuclei or other subcellular fractions. Little

is known about the mechanisms underlying acetylcho-

linesterase nucleic transportation and the restrictions on

its delivery to the cell surface. The C-terminal peptide of

acetylcholinesterase, which is critical for the membrane-

bound character of acetylcholinesterase, is probably

responsible for the distribution by virtue of its binding

with the other elements [23,24].

AChE-R is mainly a soluble and secreted form of

the enzyme due to lack of the C-terminal domain

encoded by exon 5 or 6 of the ACHE gene [25].

Similar to AChE-S, AChE-R displays variations in

cellular distribution with regard to the promotion of

cell proliferation. AChE-R was found to accumulate

in homogenate fractions enriched with membrane of

myasthenia gravis thymus, which bears a pathological

characteristic trait of thymic hyperplasia, probably the

result of an enhanced cell proliferation rate. Altera-

tions in the distribution of AChE-R may be responsi-

ble for the change in PKCbII, because a notable

enhancement in PKCbII expression was detected in

thymuses of AChE-R transgenic mice. In addition,

thymocytes of AChE-R transgenic mice were less sensi-

tive to apoptosis than were controls. It is still not

known whether the location change of AChE-R is due

to its binding with PKC [26]. Under oxidative stress

conditions, AChE-R can be secreted from glia cells

and probably promotes proliferation of the surround-

ing neurons [27]. However, the extended AChE-R vari-

ant N-AChE-R enhances the cell death induced by

light damage to photoreceptors [6]. What remains to

be established is whether the effects of N-AChE-R

occur via a reduction in AChE-R expression or

because of antagonizing effects of AChE-R by direct

insertion into the membrane with the N-terminus or

signal cascades unrelated to other acetylcholinesterase

variants. Thus, acetylcholinesterase effects related to

the promotion and inhibition of cell proliferation are

cell-type and cell-state dependent. It is also possible

that acetylcholinesterase functions are correlated with

its binding partners that are located in alternative sub-

cellular positions.

Hydrolytic activity ofacetylcholinesterase and apoptosis

The hydrolytic activity of acetylcholinesterase is essen-

tial for execution of the classical function of the

enzyme, however, it appears to be unnecessary for ace-

tylcholinesterase’s regulation of cell growth or death.

Overexpression of non-catalytic AChE-S in NRK cells

attenuated the proliferation rate and elevated sensitiv-

ity to apoptotic stimuli [28]. ARP, a peptide derived

from the C-terminus unique for AChE-R, and a

14-amino acid peptide derived from the C-terminal

of AChE-S, do not require catalytic activity to execute

the functions related to the promotion of cell prolifera-

tion or induction of apoptosis [29]. Furthermore, when

using acetylcholinesterase inhibitors in Alzheimer’s dis-

ease treatment binding to the peripheral site and not

the central catalytic active site is more effective [30].

Together, these studies indicate that sites beyond

the active center of acetylcholinesterase are critical in

modulating cell growth and death.

How does acetylcholinesteraseparticipate in apoptosis?

Acetylcholinesterase isoforms participate in apoptosis

in two ways: by promoting or suppressing cell death.

Acetylcholinesterase and apoptosis H. Jiang and X.-J. Zhang


The mechanisms underlying the involvement of acetyl-

cholinesterase in modulating cell growth and death are

not fully understood, but several models have been

proposed. Enhanced acetylcholinesterase variant

expression may influence the expression of other group

genes, including those involved in apoptosis [31]. Ace-

tylcholinesterase was suggested to function by binding

with specific partners or by influencing other elements

in the presence of apoptotic stimuli or under stress.

This may explain why overexpression of AChE-S does

not initiate but rather enhances the sensitivity to cell

death [28]. Acetylcholinesterase also contributes to the

formation of the apoptosome during apoptosis. Silenc-

ing acetylcholinesterase with siRNA blocks the inter-

action between apoptotic protease activating factor 1

and cytochrome c [32].

Acetylcholinesterase is involved in the pathogenesis

of Alzheimer’s disease, which is characterized by

amyloid fibril deposition in body tissues, increased

acetylcholinesterase staining in Alzheimer disease pla-

ques and loss of cholinergic neurons. There is still no

explicit mechanism for the toxicity of acetylcholines-

terase in Alzheimer’s disease. A 14-amino acid pep-

tide derived from AChE-S displays toxicity towards

cultured cells and is able to assemble into amyloid

fibrils under physiological conditions [29]. One possi-

ble explanation is that the conformational switch

region in the shorter acetylcholinesterase protein frag-

ments has a higher propensity for conformation con-

version from a helix to b sheet. Thus, the converted

acetylcholinesterase fragments may serve as amyloid

nuclei in amyloid b fibril formation [33]. This peptide

may also exert toxic or trophic effects by modulating

alpha7 nicotinic receptors [34]. This may explain why

acetylcholinesterase accumulates in Alzheimer’s dis-

ease plaques [35].

Unlike AChE-S, which promotes cell death, AChE-

R exerts the inverse effect by positively regulating cell

proliferation. The stress-induced AChE-R promotes

proliferation by forming a triple complex with PKCeand RACK1 [36], and ARP enhanced AChE-R levels

under stress conditions [18]. Although the relationship

between acetylcholinesterase and cell-cycle proteins

remains unknown, the cell-cycle arrest effects have

been observed in differentiating cells with acetylcholin-

esterase expression [37].

Summary and prospects

The integrated effects of acetylcholinesterase on cell

growth control and apoptosis have been reviewed

here. Certain functions of acetylcholinesterase with

regard to the modulation of cell proliferation and

cell death seem to be specific to particular acetylcho-

linesterase isoforms. The proportion of variants

changes in a manner dependent on the intensity of

the cellular response to stress. Thus, understanding

the regulation of the balance between AChE-R and

AChE-S is an important direction for future investi-

gation. How do specific acetylcholinesterase variants

achieve selectivity in modulating cell growth and

death? The answer is not clear, but their C-terminal

peptides are likely to be involved. AChE-R, as a

secreted monomer, is likely to modulate proliferation

of the neighboring cells [27] possibly by influencing

the ligands on the cell surface [38]. ARP and the

synthesized 14-amino acid peptide derived from

AChE-S represent possible means by which acetyl-

cholinesterase variants may function after being pro-

cessed and the latter may be a natural entity. The

effects of acetylcholinesterase on cell growth control

may further correlate with protein modification. The

glycosylation of acetylcholinesterase is necessary for

maintaining the stability of this enzyme [39]. In the

cerebral spinal fluid of Alzheimer’s disease patients,

a different glycosylation pattern of acetylcholinester-

ase was observed [40]. Chaperone heat shock pro-

teins excessively accumulate with overexpressed

AChE-S or downregulation of AChE-R during stress

[10,41]. The heat shock protein clusters reflect

chronic endoplasmic reticulum stress responses.

Therefore, it would be interesting to know whether

modification of acetylcholinesterase is the basis of

the stress-mediating effects of this enzyme. Consider-

ing acetylcholinesterase as a binding target, it would

be meaningful and exercisable to develop antibodies

or small molecular markers as sensitive in situ indica-

tors to distinguish apoptotic cells or cells in stress

[42]. In addition, the location and signal transduction

of acetylcholinesterase may be influenced by its part-

ners, which is probably the basis of the pathogenesis

of acetylcholinesterase-associated diseases. Using a

protein–protein comparison blast tool, cholinesteras-

es including acetylcholinesterase-related proteins were

found to be common to both Alzheimer’s disease

and diabetes, indicating the possible role of acetyl-

cholinesterase in signal transduction in insulin resis-

tance and lipid metabolism [43]. Furthermore,

anomalous acetylcholinesterase expression has been

found in tumors [44]. Therefore, elucidating the

3D structures and functions of acetylcholinesterase

variants and their partners under normal and patho-

logical conditions will provide insights into how

acetylcholinesterase contributes to disease etiology

and aid in the search for therapeutic agents targeting

acetylcholinesterase.



Acknowledgments

The authors are grateful to Dr Hermona Soreq (The

Hebrew University of Jerusalem, Israel) for her cri-

tique of the manuscript. This study was supported in

part by grants from the National Natural Science

Foundation of China (no. 30570920, 30623003), the

Third Phase Creative Program of Chinese Academy of

Sciences (no. KSCX1-YW-R-13), the Major State

Basic Research Development Program of China (973

Program, no. 2007CB947901), and the Science and

Technology Commission of Shanghai Municipality

(no. 06JC14076 and 06DZ22032).

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