Physiology, Acetylcholinesterase (2023)


Acetylcholinesterase (AChE) is a cholinergic enzyme found primarily at postsynaptic neuromuscular junctions, particularly in muscles and nerves. Instantly breaks down or hydrolyzes acetylcholine (ACh), a natural neurotransmitter, into acetic acid and choline.[1]The main function of AChE is to stop neuronal transmission and signaling between synapses to prevent ACh dispersal and activation of nearby receptors. AChE is inhibited by organophosphates and is an important component of pesticides and nerve agents.


Organophosphates are acetylcholinesterase inhibitors with potential exposure and toxicity associated with their use as pesticides. Due to their widespread use, organophosphates are one of the most common causes of poisoning from agricultural, accidental, or suicidal exposure throughout the world.[2]Exposure to organophosphates can cause symptoms such as confusion, headaches, memory impairment, and neurotoxic effects from repeated exposure. Irreversible acetylcholinesterase inhibitors used as insecticides or nerve agents in warfare show significant toxicity. These agents induce a cholinergic crisis that includes any combination of the following:

  • Muscarinic effects such as miosis, increased secretion (salivation, lacrimation), diarrhoea, urination

  • Nicotinic effects such as muscle twitching and neuromuscular blockade

  • Central effects: bradycardia

Organophosphate poisoning can be treated with atropine, an antimuscarinic agent that reduces the effects of excess ACh.[2]Atropine should be started with 2 to 5 mg i.v. for adults and 0.05 mg/kg i.v. give to children It is also appropriate to double the dose every 3 to 5 minutes until symptoms resolve if relief is not achieved after the first dose.[3]

Alzheimer's dementia (AD) is a common disease that affects memory and cognition. The pathophysiology of cognitive decline associated with AD has been attributed to loss of cholinergic neurons.[4]Histologically, B-amyloid plaques and neurofibrillary tangles disrupt synaptic signaling, leading to nerve cell death.[5]Since the 1990s, AChE inhibitors have shown some benefit for Alzheimer's disease.[6]AChE inhibition results in reduced breakdown and subsequent accumulation of acetylcholine. This excess acetylcholine results in increased stimulation of muscarinic and nicotinic receptors, providing some therapeutic relief for memory deficits in AD.[4]AChE inhibitors have differential penetration of the blood-brain barrier (BBB). Donepezil, rivastigmine, and tacrine are commonly used drugs for Alzheimer's disease with good penetration of the blood-brain barrier. This activity contrasts with the carbamate AChE inhibitors neostigmine or pyridostigmine, which are charged quaternary structures at physiologic pH that impede the passage of the blood-brain barrier.[7]While the benefits of acetylcholine modulation therapy are promising, further study is needed due to the potential for AChE accumulation, which can potentially interact with amyloid-B plaques and cause greater neurotoxicity than amyloid-B alone.[4][8]


As an enzyme, acetylcholinesterase exists as a monomer that is often polymerized into a dimer with a disulfide bond. Together with van der Waals forces, two dimers can join to become tetramers. Tetramers accumulate and attach to so-called "tails", which consist of three strands. Chemically and immunologically, these tails structurally resemble collagen and can be degraded by collagenases. Tetramer dimers are attached to each tail with an additional disulfide bond. A study by Brimijoin et al. describes the six combinations of AChE: three forms of globular structure (monomers, dimers, tetramers) and three forms of tetramers (tail, double, triple).[9]Globular AChE is marked with a "G" and caudal AChE is marked with an "A". Several forms have numerical subscripts associated with each letter to indicate the number of their catalytic subunits. For example, a globular monomer is "G1" and a globular tetramer is "G4"; while "A12" is a triple-tailed tetramer.[9]


Although AChE's main function is to terminate neural transmission, researchers have discovered that AChE also plays a role in neural development. From an embryological point of view, AChE is intrinsically involved in the development of the nervous system and is expressed in developing neurons and during periods of axonal growth (a period in which enzymatic activity does not seem to be the most important). In the peripheral nervous system of chicks, transient AChE activity was found locally in the dorsal root ganglia. These results suggest that AChE contributes to morphogenesis during fetal development in addition to its main enzymatic function.[10]

Organ Systems Involved

Acetylcholinesterase is known to distribute in nervous tissues such as the brainstem, cerebellum, peripheral and autonomic nervous systems. Skeletal muscle also contains AChE with patterns of distribution apparently related to the type of muscle (fast twitch versus slow twitch) and its specific function.[9]

The presence and function of AChE in red blood cells is less well understood. Blood group antigens are found on the outer lipid bilayer of red blood cells to facilitate antibody detection. Similarly, AChE is also present in red blood cell membranes.[11]


The neurotransmitter acetylcholine is released when a propagated neural signal excites or activates a cell membrane. Consequently, the ACh receptor undergoes a conformational change and the membrane releases calcium ions. These calcium ions play a role in the excitation of nerve and muscle fibers and trigger another change in phospholipids. In essence, the downstream effect of an ACh-initiated signal results in the amplification and propagation of cell signaling.[12]


The interaction of acetylcholinesterase with the acetylcholine substrate leads to the degradation, hydrolysis, and inactivation of acetylcholine and subsequent control of the amount of ACh in the synapse. AChE is a serine hydrolase that generates a tetrahedral intermediate through acid-base reactions with a catalytic triad (serine, histidine, acid residue).[8]Histidine allows a proton to transfer between the oxygen molecules in serine and ACh, removing choline to form a new acylated serine. When acylated serine is deacylated, regeneration of free AChE begins. In this reaction, aspartate stabilizes the protonated histidine, which releases acetic acid and a new free enzyme. The interaction between amino acid residues (tyrosine, phenylalanine, tryptophan) that form a peripheral anion site affects the conformational binding of ACh to that site.[1]

Related tests

Positron emission tomography (PET) of cortical AChE activity in vivo was used to measure the efficacy of anti-dementia therapy. There have been reports of decreased acetylcholinesterase activity in patients with Alzheimer's disease. By measuring AChE activity and using it to assess the cholinergic innervation expressed by axons and nerves, researchers can shape and assess the efficacy of cholinesterase inhibitors as they help treat Alzheimer's disease.[13]


The human brain has a confluence of cholinergic neurons that project to different cortical areas. These neurons control attention, thinking, and the processing of stimuli. Cholinergic neurons span not only the forebrain, but also the brainstem and thalamus (as the reticular nucleus), which are responsible for consciousness and attention. In the context of Alzheimer's dementia as a neurodegenerative disease, these cholinergic neurons exhibit aberrant projections that correlate with the classic symptoms of slowness and cognitive decline.[13]The disease is known for short-term memory impairment, brain atrophy, B-amyloid plaques, tangles, and tau protein deposits.[1]

clinical importance

Patients with Alzheimer's disease are usually treated with acetylcholinesterase inhibitors, which relieve symptoms by preventing ACh turnover. In fact, sustained ACh levels help to recalibrate the neurotransmitter to proper and appropriate levels.[5]Inhibition of AChE increases the concentration of ACh at the synaptic junction and allows potentiation of the signal. This effect reduces choline uptake and increases the number of M2 muscarinic receptors. A slowing of disease progression and an increase in attention span have been reported in patients treated with AChE inhibitors. However, no significant evidence of increased short-term memory has been observed in the current literature.[1]

Despite the apparent utility of AChE inhibitors for the treatment of Alzheimer's disease, recent studies state that the use of such inhibitors does not fully treat the pathology. Nordberg et al. found that some AChE inhibitors, such as donepezil or galantamine, increased AChE levels in the CSF.[14]AChE imbalance can exacerbate Alzheimer's dementia because AChE-amyloid B complexes have higher toxicity than amyloid B plaques alone.[4]These results warrant a reassessment of current treatment options, as these drugs may have the underlying potential to worsen the disease state of Alzheimer's disease.[8]



McHardy SF, Wang HL, McCowen SV, Valdez MC. Recent advances in acetylcholinesterase inhibitors and reactivators: an update of the patent literature (2012-2015).Expert opinion Ther Pat.April 2017;27(4):455-476.[PubMed: 27967267]


Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Inhibidores de la Acetilcholinesterase: Farmacologia e toxicologia.Curr Neurofarmaco.Mayo 2013;11(3):315-35.[PMC Free Article: PMC3648782] [PubMed: 24179466]


Konickx LA, Bingham K, Eddleston M. Is oxygen required before atropine administration in organophosphate or carbamate pesticide poisoning? - A cohort study.Clin Toxicol (Phila).June 2014;52(5):531-7.[Free PMC article: PMC4134047] [PubMed: 24810796]


Lazarevic-Pasti T, Leskovac A, Momic T, Petrovic S, Vasic V. Modulators of acetylcholinesterase activity: from Alzheimer's disease to anticancer drugs.Curr Med.Chem.2017;24(30): 3283-3309.[PubMed: 28685687]


Rees TM, Brimijoin S. The role of acetylcholinesterase in the pathogenesis of Alzheimer's disease.Drugs today (Barc).January 2003;39(1):75-83.[PubMed: 12669110]


McGleenon BM, Dynan KB, Passmore AP. Acetylcholinesterase inhibitors in Alzheimer's disease.Br J Clin Pharmacol.1999 October;48(4):471-80.[Losing Cost PMC Article: PMC2014378] [PubMed: 10583015]


Pohanka M. Acetylcholinesterase and butyrylcholinesterase inhibitors find t. J. Mol. scienceJune 2, 2014;quince(6):9809-25.[Cost Loser PMC Item: PMC4100123] [PubMed: 24893223]


Soreq H, Seidman S. Acetylcholinesterase: new roles for an old actor.Nat. Rev. Neurosci.April 2001;2(4):294-302.[PubMed: 11283752]


Brimijoin S. Molecular forms of acetylcholinesterase in the brain, nerves, and muscles: nature, location, and dynamics.Prog. Neurobiol.1983;21(4):291-322.[PubMed: 6198691]


Bigbee JW, Sharma KV, Gupta JJ, Dupree JL. Morphogenetic role of acetylcholinesterase in axonal growth during neural development.Environmental Health Perspective.February 1999;107 Supplement 1(Supplement 1):81-7.[PMC Free Article: PMC1566359] [PubMed: 10229710]


Bartels CF, Zelinski T, Lockridge O. The mutation at codon 322 in the human acetylcholinesterase (ACHE) gene is responsible for the YT blood group polymorphism.Bin J Hum Genet.1993 mayo;52(5):928-36.[PMC Free Article: PMC1682033] [PubMed: 8488842]


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What is acetylcholinesterase and why is it important? ›

Acetylcholinesterase, also called AChE enzyme, is a cholinergic enzyme located in the synapse between animal nerve and muscle cells. Acetylcholinesterase can also be found between two nerve cells. Its primary job is to break down acetylcholine, a major neurotransmitter, into acetic acid and choline.

What does a lack of acetylcholinesterase do? ›

Low levels of acetylcholine are associated with memory issues and muscle disorders. Cholinesterase inhibitors are used to treat Alzheimer's disease and myasthenia gravis. The benefits of a choline supplement have yet to be fully determined.

What causes acetylcholinesterase to be released? ›

The release of acetylcholine occurs when an action potential is relayed and reaches the axon terminus in which depolarization causes voltage-gated calcium channels to open and conduct an influx of calcium, which will allow the vesicles containing acetylcholine for release into the synaptic cleft.

How is acetylcholinesterase activated? ›

Acetylcholinesterase is found in the synapse between nerve cells and muscle cells. It waits patiently and springs into action soon after a signal is passed, breaking down the acetylcholine into its two component parts, acetic acid and choline.

What happens when a drug inhibits acetylcholinesterase? ›

The inhibition of the enzyme leads to accumulation of ACh in the synaptic cleft resulting in over-stimulation of nicotinic and muscarinic ACh receptors and impeded neurotransmission. The typical symptoms of acute poisoning are agitation, muscle weakness, muscle fasciculations, miosis, hypersalivation, sweating.

What happens if there is too much acetylcholinesterase? ›

Excessive accumulation of acetylcholine (ACh) at the neuromuscular junctions and synapses causes symptoms of both muscarinic and nicotinic toxicity. These include cramps, increased salivation, lacrimation, muscular weakness, paralysis, muscular fasciculation, diarrhea, and blurry vision.

What is the benefit of acetylcholinesterase? ›

AChEIs have proven to be beneficial in improving the underlying cholinergic system deficits in AD and LBD, and they have an important role in treating cognitive and behavioral symptoms of these neurodegenerative disorders.

What would happen if the acetylcholinesterase enzyme are destroyed by drugs? ›

Drugs that inactivate acetylcholinesterase and thereby prolong the presence of acetylcholine in the cleft can lead to repetitive firing of the muscle cell

What destroys acetylcholinesterase? ›

Answer and Explanation: The enzyme that destroys acetylcholine (ACh) is called acetylcholinesterase. This enzyme is found embedded on the membrane of the end terminal on the pre-synaptic neuron.

How do you increase acetylcholinesterase naturally? ›

Choline is an essential nutrient and a building block of acetylcholine. Foods that are naturally high in choline include whole eggs, meats and fish, and whole grains. Studies in laboratory animals and humans suggest that consuming foods or supplements rich in choline may elevate levels of acetylcholine in the brain.

What is the difference between acetylcholine and acetylcholinesterase? ›

Acetylcholinesterase (AChE) is a cholinergic enzyme primarily found at postsynaptic neuromuscular junctions, especially in muscles and nerves. It immediately breaks down or hydrolyzes acetylcholine (ACh), a naturally occurring neurotransmitter, into acetic acid and choline.

What drugs increase acetylcholinesterase? ›

List of Cholinesterase inhibitors
Drug NameAvg. RatingReviews
Exelon (Pro) Generic name: rivastigmine6.115 reviews
Namzaric (Pro) Generic name: donepezil / memantine8.86 reviews
Aricept ODT Generic name: donepezil7.53 reviews
Razadyne ER Generic name: galantamine102 reviews
6 more rows

What is a drug that inactivates acetylcholinesterase? ›

Metrifonate or trichlorfon is an irreversible organophosphate acetylcholinesterase inhibitor.

Is acetylcholinesterase sympathetic or parasympathetic? ›

ACh is the chief neurotransmitter of the parasympathetic nervous system, the part of the autonomic nervous system, that contracts smooth muscles, dilates blood vessels, increases bodily secretions, and slows heart rate.

How do you inhibit acetylcholinesterase? ›

Most uses of cholinesterase inhibitors are based on a common mechanism of action initiated by inhibition of acetylcholinesterase (AChE). Extensive inhibition of this enzyme leads to accumulation of the neurotransmitter acetylcholine and enhanced stimulation of postsynaptic cholinergic receptors.

What food is an acetylcholinesterase inhibitor? ›

The most common naturally occurring cholinesterase inhibitors, the SGAs, are found in plants of Solanaceae such as potato, eggplant, and tomato. The main SGAs in potatoes are α-solanine and α-chaconine, both triglycosides of solanidine, a steroidal alkaloid derived from cholesterol (Figure 2).

How do anticholinesterase drugs work? ›

Anticholinesterases increase the residence time of acetylcholine in the synapse. This allows rebinding of the transmitter to nicotinic receptors. It thus gives acetylcholine the competitive advantage over the neuromuscular blocking agent.

What is the most common side effect of acetylcholinesterase? ›

The most common adverse effects of cholinesterase inhibitors include nausea, diarrhea, vomiting, decreased appetite, dyspepsia, anorexia, muscle cramps, fatigue, insomnia, dizziness, headache, and asthenia.

How does acetylcholine make you feel? ›

Acetylcholine tells muscles to twitch and more, but it also tells your hippocampus to store a memory. It plays an essential role in alertness, attention, learning, and memory. It's so essential to memory, in fact, that acetylcholine deficits are associated with Alzheimer's disease.

Why is acetylcholinesterase used for Alzheimer's? ›

Donepezil, rivastigmine and galantamine all prevent an enzyme called acetylcholinesterase from breaking down acetylcholine. This means there is a higher concentration of acetylcholine in the brain, which leads to better communication between nerve cells. This may ease some symptoms of Alzheimer's disease for a while.

What are the drawbacks of acetylcholinesterase inhibitors? ›

The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances.

Why do acetylcholinesterase inhibitors help dementia? ›

Cholinesterase inhibitors result in higher concentrations of acetylcholine, leading to increased communication between nerve cells, which in turn, may temporarily improve or stabilise the symptoms of dementia.

Why does acetylcholinesterase cause paralysis? ›

Increased acetylcholine at nicotinic sites at the neuromuscular junction causes muscle fasciculations and flaccid paralysis due to excess acetylcholine at the neuromuscular junction. Excess acetylcholine in the brain patients may cause headache, insomnia, giddiness, confusion, and drowsiness.

What happens when acetylcholinesterase goes through the aging process? ›

The extent of potential reactivation of organophosphate-inhibited acetylcholinesterase decreases with time, a phenomenon called ageing. Ageing is due to dealkylation of the alkoxyl group of the residue bound to the enzyme. The rate of ageing is proportional to the electron-donating capacity of the alkyl group.

Does coffee increase acetylcholine? ›

Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 receptors.

Which vitamin produces acetylcholine? ›

Choline is a water‐soluble B‐group vitamin, which humans must consume through their diet to remain healthy. Meat, eggs and yeast extract are great sources of choline, an essential component of cell membranes and also the precursor of the neurotransmitter acetylcholine (ACh).

What vitamin increases acetylcholine? ›

Vitamin B1 slightly increased the synthesis of acetylcholine in low concentrations and decreased it in higher ones.

Does acetylcholinesterase cause Alzheimer? ›

Recently, however, AChE itself has been implicated in the pathogenesis of Alzheimer's disease. In particular, it appears that AChE may directly interact with amyloid-beta in a manner that increases the deposition of this peptide into insoluble plaques.

What is another name for acetylcholinesterase? ›

The main type for that purpose is acetylcholinesterase (also called choline esterase I or erythrocyte cholinesterase); it is found mainly in chemical synapses and red blood cell membranes.

Can you supplement acetylcholine? ›

Acetylcholine can't be taken as a dietary supplement. However, supplements that increase the release of acetylcholine, such as choline supplements, and those that inhibit the breakdown of acetylcholine may boost acetylcholine levels.

Where can I get acetylcholinesterase? ›

Acetylcholinesterase (AChE) is a cholinergic enzyme primarily found at postsynaptic neuromuscular junctions, especially in muscles and nerves.

Does nicotine inhibit acetylcholinesterase? ›

It has been demonstrated that nicotine interferes with acetylcholine, which is the major neurotransmitter of the brain. Acetylcholine can bind to two different kinds of receptors: nicotinic receptors, which are activated by nicotine, and muscarinic receptors, which are activated by muscarine.

What decreases acetylcholine? ›

Some natural compounds like forskolin and lipoic acid may reduce acetylcholine activity or levels. They are collectively known as anticholinergics.

Is acetylcholinesterase excitatory or inhibitory? ›

ACh has excitatory actions at the neuromuscular junction, at autonomic ganglion, at certain glandular tissues and in the CNS. It has inhibitory actions at certain smooth muscles and at cardiac muscle.

What happens when acetylcholine is released? ›

Acetylcholine is the chief neurotransmitter of the parasympathetic nervous system, the part of the autonomic nervous system (a branch of the peripheral nervous system) that contracts smooth muscles, dilates blood vessels, increases bodily secretions, and slows heart rate.

How does acetylcholine affect the brain? ›

Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons.

What are the best acetylcholinesterase inhibitors? ›

60. The three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine as monotherapies are recommended as options for managing mild to moderate Alzheimer's disease under all of the conditions specified in 62 and 63. 61.

What is the role of acetylcholinesterase in muscle contraction? ›

It closes the neuromuscular junction to stop a muscle contraction.

What does acetylcholinesterase do to the heart? ›

Acetylcholine slows the heart rate by activating the M2 muscarinic receptor (M2R) that, in turn, opens the acetylcholine-activated potassium channel (IK,ACh) to slow the firing of the sinus node.

What builds up in the brain causing Alzheimer's? ›

Alzheimer's disease is thought to be caused by the abnormal build-up of proteins in and around brain cells. One of the proteins involved is called amyloid, deposits of which form plaques around brain cells. The other protein is called tau, deposits of which form tangles within brain cells.

What are the three acetylcholinesterase inhibitors? ›

Donepezil, rivastigmine and galantamine all prevent an enzyme called acetylcholinesterase from breaking down acetylcholine in the brain.


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