Cholinesterase inhibitors and acetylcholine in Alzheimer's disease
Cholinesterase inhibitors block acetylcholinesterase, the enzyme that breaks down acetylcholine, which raises its concentration in the synapse and eases the symptoms of Alzheimer's disease.
Remember
Block the enzyme that breaks acetylcholine down and more acetylcholine stays in the synapse, which eases the symptoms of Alzheimer's disease.
Memory aid
acetylcholinesterase is the clean-up enzyme for acetylcholine
Blocking the clean-up enzyme leaves more acetylcholine in the gap.
Acetylcholine (ACh) is a neurotransmitter. In the brain it is involved in arousal, learning and memory. It is also the neurotransmitter at the neuromuscular junction (the synapse between a motor nerve and a muscle), and it is the main one used by the parasympathetic nervous system.
Alzheimer's disease is a form of dementia, in which mental function deteriorates. In it, the cholinergic system (the neurons that use ACh) is impaired, so there is less ACh signalling.
Once ACh has been released, it is broken down in the synaptic cleft (the gap between neurons) by the enzyme acetylcholinesterase. Cholinesterase inhibitors, such as donepezil, galantamine and rivastigmine, block that enzyme. ACh then persists for longer, its concentration in the synapse rises, and transmission is strengthened in the cholinergic pathways that survive.
Cholinesterase inhibitors act on the breakdown of ACh, not on its synthesis. The cholinesterase inhibitors used in Alzheimer's disease do not act on the release step, they do not activate receptors directly, and they raise acetylcholine rather than block its receptors. Their effect comes from keeping the ACh that is already released around for longer.
They treat symptoms rather than cure the disease, and NICE recommends them as options for mild to moderate Alzheimer's disease.
Key facts
- Normal fate of ACh
- it is broken down in the synaptic cleft by acetylcholinesterase.
- Drug action
- cholinesterase inhibitors block acetylcholinesterase, raising synaptic acetylcholine.
- Examples
- donepezil, galantamine and rivastigmine.
- Use
- symptomatic treatment of mild to moderate Alzheimer's disease.
- What is impaired
- the cholinergic system, the neurons that use ACh, so there is less ACh signalling.
Exam traps
- Cholinesterase inhibitors act on breakdown, not on synthesis, and reducing acetylcholine synthesis would deepen the cholinergic deficit.
- Cholinesterase inhibitors do not stimulate dopamine receptors directly, because they act on acetylcholine: the main deficit being treated in Alzheimer's disease is in acetylcholine signalling, while dopamine pathways contribute to motor control and to mood, arousal and reward.
- Monoamine oxidase is an enzyme that breaks down monoamines such as dopamine, not acetylcholine, because acetylcholine is broken down by acetylcholinesterase.
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