Physiology, Acetylcholinesterase (2023)

Introduction

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.

Affair

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]

cell

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]

developing

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]

profession

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]

Mechanism

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]

pathophysiology

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]

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references

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10

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11

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14

Nordberg A, Darreh-Shori T, Peskind E, Soininen H, Mousavi M, Eagle G, Lane R. Differential cholinesterase inhibitory effects on CSF cholinesterases in Alzheimer's patients.Curr Alzheimer Res.February 2009;6(1):4-14.[PMC Free Article: PMC4046577] [PubMed: 19199870]