Figures & data
(A) Normal cortical cholinergic and glutamergic neurotransmission. Cholinergic innervation of glutamatergic cortical pyramidal neurons is provided by cells in the nbM in the basal forebrain. Acetylcholine (ACh) is released following depolarization to act on nicotinic and muscarinic receptors located on glutamatergic neurons, with neurotransmitter action being terminated by AChE. Glutamatergic neurons also receive innervation from other glutamatergic cortical pyramidal neurons – in this case, released glutamate acts on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and NMDA receptors and action is terminated mostly by the reuptake of glutamate into associated glial cells. (B) Changes that occur in Alzheimer’s disease (AD). In AD atrophy and dysfunction of cholinergic and glutamatergic pyramidal neurons occurs such that remaining cortical neurons receive less innervation and consequently are less likely to be depolarized by synaptic signals. Signal-to-noise ratio at glutamatergic synapses would be reduced by a combination of a weaker ‘signal’ (from ACh and glutamate release in response to depolarization) and greater ‘noise’ (caused by an increased concentration of glutamate in the synaptic cleft between synaptic activation, due to partial failure of reuptake mechanisms). (C) The proposed mechanism of action of AChEIs and memantine with respect to the changes in AD. The use of AChEIs in AD is proposed to return the concentration of ACh in the synapse towards the normal level by reducing its breakdown, and thereby increasing the chance of the interaction of ACh with cholinergic receptors on glutamatergic pyramidal neurons. Memantine is proposed to reduce ‘noise’ at glutamatergic synapses by preventing the NMDA receptors from responding to the increased concentrations of glutamate present in the synaptic cleft between synaptic activation. In combination, it is proposed that the AChEIs and memantine would have their individual effects, but the potential for synergistic action occurs because an improved signal-to-noise ratio at glutamatergic synapses in the nbM would be expected to increase the firing rate of cholinergic neurons, and AChE inhibition would enhance this effect.
†Glutamate receptor; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor has been excluded for clarity.
ACheE: Acetylcholinesterase; AChEI: Acetylcholinesterase inhibitor; ACh-r: Acetylcholine receptor; nbM: Nucleus basalis of Meynert; NMDA-r: NMDA receptor.
Left part of each panel adapted with permission from [Danysz W, Unpublished Data].
![Figure 1. Normal cortical cholinergic and glutamatergic neurotransmission, changes that occur in Alzheimer’s disease, and the proposed mechanism of action of acetylcholinesterase inhibitors and memantine with respect to these changes.(A) Normal cortical cholinergic and glutamergic neurotransmission. Cholinergic innervation of glutamatergic cortical pyramidal neurons is provided by cells in the nbM in the basal forebrain. Acetylcholine (ACh) is released following depolarization to act on nicotinic and muscarinic receptors located on glutamatergic neurons, with neurotransmitter action being terminated by AChE. Glutamatergic neurons also receive innervation from other glutamatergic cortical pyramidal neurons – in this case, released glutamate acts on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and NMDA receptors and action is terminated mostly by the reuptake of glutamate into associated glial cells. (B) Changes that occur in Alzheimer’s disease (AD). In AD atrophy and dysfunction of cholinergic and glutamatergic pyramidal neurons occurs such that remaining cortical neurons receive less innervation and consequently are less likely to be depolarized by synaptic signals. Signal-to-noise ratio at glutamatergic synapses would be reduced by a combination of a weaker ‘signal’ (from ACh and glutamate release in response to depolarization) and greater ‘noise’ (caused by an increased concentration of glutamate in the synaptic cleft between synaptic activation, due to partial failure of reuptake mechanisms). (C) The proposed mechanism of action of AChEIs and memantine with respect to the changes in AD. The use of AChEIs in AD is proposed to return the concentration of ACh in the synapse towards the normal level by reducing its breakdown, and thereby increasing the chance of the interaction of ACh with cholinergic receptors on glutamatergic pyramidal neurons. Memantine is proposed to reduce ‘noise’ at glutamatergic synapses by preventing the NMDA receptors from responding to the increased concentrations of glutamate present in the synaptic cleft between synaptic activation. In combination, it is proposed that the AChEIs and memantine would have their individual effects, but the potential for synergistic action occurs because an improved signal-to-noise ratio at glutamatergic synapses in the nbM would be expected to increase the firing rate of cholinergic neurons, and AChE inhibition would enhance this effect.†Glutamate receptor; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor has been excluded for clarity.ACheE: Acetylcholinesterase; AChEI: Acetylcholinesterase inhibitor; ACh-r: Acetylcholine receptor; nbM: Nucleus basalis of Meynert; NMDA-r: NMDA receptor.Left part of each panel adapted with permission from [Danysz W, Unpublished Data].](/cms/asset/b6d362fd-bd56-4dc1-b108-574a853538e9/iern_a_11212852_f0001_b.jpg)