Acetylcholine Structure, Function, Physiology, and Dysfunction

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Acetylcholine[edit]

The discovery of acetylcholine (ACh) a hundred years ago by two Nobel laureates laid down the foundation of chemical transmission. Otto Loewi termed ACh ‘vagusstoof’ for its ability to slow down the heart rate in response to vagal stimulation. ACh was later identified by Henry Dale as a naturally occurring chemical substance in the nervous system.[1][2] Since then, ACh has been the focus of tremendous research that has elucidated its functions in the brain and periphery. It plays a key role in centrally mediated cognitive functions, regulating attention, memory, learning, sleep/wake cycle, stress, depression, and aging; is the main neurotransmitter at the neuromuscular junction; and is deployed peripherally in the autonomic nervous function.[3][4][5][6][7][8] The deterioration of cholinergic system represents a key characteristic of neurodegenerative disorders that result in dementia, such as with Alzheimer’s disease, and the disruption of cholinergic signaling underlies a significant proportion of cognitive dysfunction associated with these pathologies.[3]

Figure 1. Cartoon illustration of an acetylcholine synapse. The image shows pre- and post-synaptic muscarinic (mAChR) and nicotinic (nAChR) acetylcholine receptors. (Public domain image accessed May 8, 2023)  

ACh mediates its actions via pre- and post-synaptic receptors that are widely distributed in distinct regions of the nervous system (Figure 1). It functions to alter neuronal excitability, affecting synaptic transmission and plasticity and helps to shape the coordinated activity of neurons.[9] ACh is a classic neurotransmitter with rapid, point-to point synaptic transmission and additionally participates on longer time scales in volume transmission.[9] In this way it functions as a neuromodulator, as it regulates and defines the state of neuronal networks in different regions of the brain and modifies and shapes their response to internal and external stimuli. These functions of ACh and its influence on enduring changes at the mRNA and gene expression level, is consequential for effective brain function from the neuronal level to the development of pathological states, such as Alzheimer’s disease.

Evidence points to ACh having an outsized role in the survival and behavior of an organism. Basal forebrain and brainstem cholinergic projections underlie its central functions and disruptions of this system is implicit in many conditions, including age-related cognitive deficits, dementia, Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, addiction, nicotine dependance, and pain modulation.[3][10][11] Technological advancements - that allow for the selective manipulation of cholinergic neurons, receptors, and circuits; the continuing improvements in spatiotemporal resolution in detecting changes in chemical and electrophysiological rhythms; ease of use of genetic arrays to inform gene expression, the development of novel, genetically encoded ACh sensors; imaging and computational models; and optogenetic stimulation in awake and behaving animals - enable us to probe deeper into the cholinergic system, looking at its endogenous release, influence on and regulation of signaling involving cognitive functions and other behaviors.[12][13][14] These advancements also allow us to tease out the role of ACh in neurodegenerative diseases.  

Many cholinergic neurons are known to co-localize and release GABA and glutamate, and could function synergistically with these neurotransmitters. For example, the mammalian spinal motor neurons release ACh at the neuromuscular junction to evoke muscle contractions, additionally their central collaterals release glutamate to excite inhibitory Renshaw cells and other motor neurons[15] This feedback circuitry deploying 2 neurotransmitters may have the intended effect of stabilizing and optimally integrating the activity of different neurons in the central loop, which in contrast is effectively carried out solely by ACh at the periphery. Additionally, direct cholinergic projections from the globus pallidus externus (GPe), a basal ganglia nucleus that is under striatal control, activates the frontal cortex and co-releases GABA.[16] This direct pathway is inhibited by the indirect, dopamine (D2) receptor sensitive striatal projections. The interaction of the indirect pathway with the direct GPe mediated activity in the frontal cortex could have unintended consequences for neuropsychiatric treatments that targets basal ganglia dopamine receptors. These examples highlight an important issue that in discrete regions of the brain, the activity of cholinergic and co-localized neurotransmitters or peptides makes for interpretation of behavioral analysis ostensibly unique.

ACh is a ubiquitous, and apart from its function as a neurotransmitter influencing the internal and external cellular processes and responses, it is present as a signaling agent in non-neuronal cells – the non-neuronal cholinergic system (NNCS) - where dysregulation can have a pernicious effect on disease consolidation and progression related to skin, lungs, heart, immune system, intestinal epithelium, urinary, and reproductive systems.[17][18] It appears to have a paradoxical role in inflammation, where it is anti-inflammatory in protection against sepsis, and conversely promotes inflammation to fend off a viral infection.[19] ACh is released from the T-cells in the spleen in response to vagal nerve stimulation (VNS), and is essential to the circuit that forms this inflammatory reflex that is important in protecting against sepsis. Additionally, ACh released from the immune system T cells induces vasodilation that is essential for their response against viruses and for T cell migration to sites of infection.[19] ACh is also found widely in single celled organisms such as fungi and bacteria, and in plants, where ACh function is not as well characterized.

With respect to its role in cognition, recent imaging and electroencephalogram studies have documented ACh status as a relevant index for determining and stratifying cognitive ability in humans. Monitoring ACh in vivo, can serve as a marker for diagnosis, tracking disease progression, and assessing the effects of pro-cognitive agents.[20][21] The compounds that elevate ACh neurotransmission are widely used to improve cognitive function in neurodegenerative conditions, including for improving memory, learning and attention.

Synthesis and Metabolism[edit]

Figure 2. Acetylcholine Chemical Structure. (Public domain image accessed on April 25, 2023.)

Acetylcholine is a small molecule formed as an ester of choline and acetic acid (Figure 2). It is synthesized in neurons and non-neuronal cells from substrates choline and acetyl coenzyme A (COA), in a reaction catalyzed by the enzyme, choline acetyltransferase (ChAT).[22] Choline, necessary for ACh synthesis, is an essential amino acid and needs to be obtained from the diet. Foods such as egg yolks, vegetable seeds, legumes, and liver are good sources of choline. It is a charged particle that cannot diffuse into cells and therefore requires active uptake into cholinergic terminals via sodium-dependent transporters.[23]

The transporters transit choline through the blood-brain barrier, serving as a rate-limiting step in central ACh synthesis and neurotransmission.[24] They differ in their affinity for choline, their distribution patterns, and sodium dependency. The choline transporter CHT1 (SLC5A7; solute carrier family 5 member 7) found in cholinergic neurons, has a high affinity for choline and is essential for the maintaining optimal ACh levels for effective neurotransmission.[25] Regions with high levels of choline transporters and ACh innervation compared to regions with lower levels, could ostensibly continue to synthesize and replenish ACh when conditions demand it. Such regional differences and availability of higher extracellular levels of ACh, could be consequential for neurotransmission and moreover functionally for the modulation of brain function.  

The availability of acetic acid derived from mitochondrial acetyl COA, and choline from plasma or reuptake from synaptic cleft represent rate-limiting steps in ACh synthesis. Once synthesized, ACh is loaded into presynaptic vesicles by the vesicular ACh transporter (VAChT).[26] This transporter shares a high degree of homology with other neurotransmitter transporters, such as vesicular monoamine transporters (VMAT1 and 2). VAChT uses the electrochemical gradient generated by V-type proton ATPase to transport and accumulate ACh in the presynaptic terminals that is loaded into synaptic vesicles. Thousands of ACh molecules are loaded into synaptic vesicles representing a quantum of released ACh.[27][28]

The half-life of ACh released from the presynaptic terminal into the synaptic cleft is short and its action is rapidly terminated, within milliseconds, via hydrolysis by acetylcholinesterase (AChE), a serine hydrolase.[29][30] AChE (EC 3.1.1.7), according to the International Union of Biochemistry and Molecular Biology (IUBMB) belongs to a family of hydrolases that act on ester bonds of esters of carboxylic acids.[31][32] AChE Inhibitors (AChEIs) reversibly target this enzyme in the treatment of Alzheimer’s disease to improve cognitive function. This boosts ACh levels for signaling in the face of deteriorating forebrain cholinergic neurons and tone.[33] Drugs that fall into the category of AChEIs, such as donepezil, galantamine, and rivastigmaine, are the best line of treatments to ameliorate cognitive ability and improve the global state of AD patients.[34][35]

Acetylcholine Receptors[edit]

Acetylcholine exerts its effects by acting on two very different receptor types, the muscarinic G-protein coupled receptors (mAChRs) and the ligand-gated ion channel nicotinic receptors (nAChRs).[36] Both are present in the central and peripheral nervous systems, with the nAChRs additionally present in neurons from the sympathetic ganglia, at the neuromuscular junction, and non-neuronal cells. Due to their wide distribution underlying various functions, both receptor types have been implicated in the pathophysiology of psychiatric and neurological disorders.

Muscarinic Receptors[edit]

The muscarinic ACh receptors (mAChRs) are so named, as they are activated by mucarine, a toxin from the mushroom Amanita muscaria. These AChRs are inactivated by the toxin atropine, an alkaloid from the poisonous plant Atropa Belladonna, a member of the nightshade family. Techniques such as, X-ray crystallography, molecular cloning, receptor binding assays, imaging, to name a few, have yielded insights into the structure, function, physiology, and distribution of mAChRs. Crystal structure reveals the conformation of the receptor both in its active and inactive states, as well as its orthosteric conventional ACh binding site and outer allosteric sites. Detailed structure-function and pharmacological analysis help to guide the development of drugs specifically targeted to these binding sites for therapeutic purposes.[37]

Figure 3. Side view illustrating a ribbon diagram of the muscarinic AChR showing the color coded 7 transmembrane domains. (Public domain image accesses May 8, 2023)

The mAChRs are metabotropic and belong to class A G-protein coupled receptor family and are integral membrane proteins with 7 transmembrane domains that form a high affinity binding pocket (Figure 3). The 5 functionally distinct subtypes (M1 – M5) are encoded by separate genes and are differentially expressed in the brain and periphery.[36] They are highly expressed in the caudate and putamen compared to other parts of the brain. The subtypes are classified as such based on their individual distribution patterns, receptor conformation, and coupling with intracellular signaling partners.[38] M1, M3, M5 mAChRs are excitatory and elevate ACh signaling, whereas M2 and M4 receptors function to inhibit ACh release. Binding to these receptors activates intracellular guanine triphosphate (GTP) binding regulatory proteins - heterotrimeric G-proteins – composed of a αβγ subunits. The canonical signaling cascade is initiated by binding of extracellular ACh to these receptors and is amplified intracellularly by the G-proteins. Engaging the receptor causes it to undergo a conformational change that promotes the dissociation of the α from the βγ subunits and requires the conversion of GDP to GTP. This enables the activated α subunit to engage with effector proteins and initiate a multitude of signaling cascades with myriad effects that amplify the initial cholinergic signal. It is evident that apart from their primary mode of transducing ACh signals, mAChRs are capable, depending on the specific cell type, of activating multiple different pathways.[39][40]

M1, M3, M5 mAChRs are excitatory and couple to the pertussis toxin-insensitive, heterotrimeric Gq G-protein family.[38] Binding to these receptors activates phospholipase C (PLC), triggering the hydrolysis of the membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2) and release of reaction products inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) into the cytoplasm that each convene different actions. IP3 binds to its receptor on the endoplasmic reticulum to release sequestered intracellular calcium, elevating the ion concentration in cells. Whereas DAG activates protein kinase C (PKC) and leads to the phosphorylation of a multitude of proteins in the signaling cascade.

The post-synaptic M1 mAChRs are prominently expressed in the frontal, temporal, parietal, and occipital cortices, and are found in other regions including the hippocampus, striatum, amygdala, and thalamus. They account for 35%-60% of all mAChR’s in the brain.[41] mAChRs are important for learning and memory, and markedly potentiate NMDA receptor mediated plasticity in hippocampal pyramidal cells.[42] Activity-dependent synaptic plasticity is dynamically modulated, strengthening neural connections that form the basis for these cognitive processes. Additionally, M1 receptors, although present in all cortical lamina, are more densely expressed in layers III and V/VI, where they are found on excitatory pyramidal cells.[43] With its association with learning and memory, the M1 receptor has garnered immense interest as a therapeutic target. Of note, M1 mAChR agonists modulate the proteolysis of amyloid precursor protein (APP), that forms β-amyloid (amyloid-β peptide; Aβ), a cardinal feature of Alzheimer’s disease. M1 agonists, reduce hippocampal and cortical Aβ and tau pathologies, and improve cognitive function in animal models of AD.[44][45] Developing selective M1 receptor targeted drugs is a challenge due to the shared homologies between the different mAChRs. It remains an intractable problem to specifically address the receptor without having dose-limited, ‘off-target’ side-effects.[45] However, allosteric modulators of the receptor that up-regulate ACh neurotransmission are being developed and clinically trialed. These should prove to be promising therapeutic agents for the treatment of AD and other conditions related to the dysfunction of the M1 and other mACh receptors.[46]

M3 mAChRs are expressed at lower levels in the brain and overlap with M1 and M4 mAChRs in the hippocampus, striatum and cortex. They are active primarily in the contraction of peripheral smooth muscles (e.g, airway, iris, ileum), endocrine, and exocrine (saliva secretion) function, and are expressed in pancreatic β-cells. In the brain they regulate insulin secretion, making them a target for investigating the mechanism of diabetes mellitus.[47]

M5 mAChRs are mostly integrated with dopamine-rich areas and constitutes just about 2% of total mAChRs in the brain. The presence of M5 receptors in the mesolimbic pathways, especially the dopaminergic ventral tegmental, an area crucial for reward-seeking behavior has generated interest in targeting the receptor for treatment of drug addiction.[48]

The inhibitory M2 and M4 mAChRs, on the other hand signal predominantly via the pertussis toxin-sensitive Gi/o G-protein family.[38][49] They inhibit adenylyl cyclase, impede the production of cAMP, inactivate protein kinase A (PKA) and downstream signaling pathways. Furthermore, they exhibit multitude effects on ion channels to influence K+ and Ca2+ ion fluxes.

M2 receptors are expressed as autoreceptors in the striatum, cerebellum, thalamus, amygdala, and hippocampus. Stimulation of these receptors depresses ACh release from pre-synaptic sites and compromises working memory. Therefore, approaches that tackle this receptor for memory and cognitive improvement have potential, but are of limited use so far due to the lack of specificity of this receptor class.[50] Additionally, the G-protein coupled inwardly rectifying K+ (GIRK) ion channels are activated by M2 mAChRs via independent binding of the G-protein βγ subunits. These subunits are released from the heterotrimeric Gi upon ACh binding, and serve to directly open the GIRK channels independently of the α-subunit.[51] M2 mAChRs play a role in reducing heart rate and the force of contraction. Drugs designed to target this subtype to ameliorate memory need to be highly selective for the brain, in order to circumvent an ‘off-target’ adverse cardiovascular effect.[50]

The M4 mAChRs are also expressed as autoreceptors and have been shown to regulate dopamine neurotransmission in the striatum. This receptor subtype is being investigated for its role in Parkinson’s disease (PD)-related and other locomotor deficits. Specifically, in animal models the M4 activity is complicit in locomotor-stimulating disorders and novel agents that block its activity demonstrate anti-parkinsonian and anti-dystonic efficacy.[52]

Nicotinic Receptors[edit]

The nicotinic ACh receptor (nAChRs) was the first neurotransmitter receptor to be isolated and biochemically characterized in the nervous system.[53] Pioneering studies at the turn of the 20th century on the action of nicotine and curare at the neuromuscular junction, established the concept of a ‘receptive substance’, later termed the nicotinic ACh receptor.[54][55] This early work led to the discovery of the quantal nature of ACh release, laying down the foundation of synaptic transmission. nAChRs are widely distributed in the central and peripheral nervous systems and immune system, as well as various peripheral tissue.[56] These receptors subserve a variety of functions mediating diverse physiological processes, including cognitive functions, anxiety, central processing of pain, and nicotine addiction.[57][58][59][60] 

Figure 4. Illustration of ribbon diagram of nicotinic AChRs. Left - Top view of the cation-selective pore, with colors indicating the different subunits. Right - Side view of the receptor. (Public domain image accessed on May 8, 2023)

The ionotropic nAChRs are ligand-gated ion channels (LGIC), belonging to the cys-loop superfamily of receptors, and consist of 5 subunits that form a central cation-selective pore (Figure 4).[61] nAChRs are highly conserved and currently 16 distinct subunits have been identified in the human proteome, 11 of which are neuronal (α2-α7, α-9, α-10, β2-β4) and 5 muscular (α-1, β-1, γ, δ, ε) isoforms.[62] The nAChR subunits are encoded with the following human genes CHRNA1-7, CHRNA9, CHRNA10, CHRNB1-4, CHRNG, CHRND, and CHRNE, respectively. nAChRs always have two or more α-subunits that are essential for ACh binding. Each of the receptor subunits forming the pentamer share a common structural motif, and contain 4 transmembrane domains (TMD), with an extracellular ligand binding N-terminal, a large intracellular loop between TMD3 and TMD4, and a relatively short extracellular C-terminal. The receptor binding site for ACh is located between the N-terminal domain of the α-subunit and the adjacent subunit in the assembly. Cys-loop receptors, which includes GABAA, glycine, and serotonin 5-HT3 receptors, are characterized by an extracellular N-terminal loop at the entrance of TMD1, formed by the disulfide bond of cysteine residues. The Cys-Cys pair is essential for agonist binding and designates the α-subunit versus other non-α subunits.[56] Like other ligand-gated ion channel receptors, the nAChRs undergoes a gating cycle from closed resting, inactive conformation, to an active agonist stabilized state, followed by a closed desensitized state. Assembled from the extensive family of different subunits, nAChRs form multiple receptor types, each with distinct pharmacological and electrophysiological profiles, gating kinetics, and spatial distribution.[11] Neuronal nACHrs found at the neuromuscular junction are similar and they are essential for regulating neuronal excitability and neurotransmission.[63]

Figure 5. Illustration of an example of subunits forming hetero- (top) and homo-pentameric (bottom) nicotinic AChRs. The ACh binding site is denoted on the α-subunits. (Public domain image accessed on May 8, 2023)

The functionally expressed human receptors form homopentamers or heteropentamers of which the α7* (*refers to supplemental subunits, eg., additional α- and β-subunits that could alter function), and α4β2* receptors, respectively, are more predominant, accounting for ~90% of cortical nAChRs (Figure 5).[64][65] These receptors have distinct physiological properties and underlie diverse functions in the mammalian nervous system. Dysfunction in these receptors is associated with a variety of disorders, such as Alzheimer’s (AD) and Parkinson’s (PD) disease, schizophrenia, depression, anxiety, attention deficit hyperactivity disorder (ADHD), addiction, and myasthenia gravis, an autoimmune neuromuscular syndrome.[66][57][64][65][67] β2-containing nAChRs are desensitized and upregulated by chroninc smoking, and it has been suggested that these receptors may contribute to both the reward and withdrawal symptoms associated with nicotine.[68] Other nACHRs found in the mammalian nervous system, including in humans, are mainly the ganglionic α3β4 nAChRs in the PNS, with other receptors subunits distributed at lower levels in different brain regions.

nAChRs are essential for cognitive functions and different nAChRs contribute to different aspects of the process and underlying synaptic plasticity. The hippocampal afferents to the medial prefrontal cortex (mPFC) are important for associative recognition - associating an object with the particular location. Synaptic plasticity when encoding information by the hippocampal-mPFC is mediated by α7* receptors, and the subsequent retrieval of the information by the α4β2* nAChRs.[69] During encoding, high concentrations of ACh recruit the low-affinity α7* receptors on cortical layer V pyramidal neurons, and along with hippocampal inputs, increase calcium influx and induce LTP at the synapse. Lower more diffuse ACh concentrations could be essential during consolidation and retrieval. This could favor activation of high-affinity α4β2* receptors that are found exclusively on interneurons in layers II/III and V, and would induce the release of GABA on layer V pyramidal cells, reducing the glutamatergic drive and inducing LTD during the memory retrieval phase.[69] Understanding the type of memory deficiency is crucial as these nAChRs contribute differently to different aspects of memory, i.e., its encoding and retrieval. This knowledge would offer more targeted interventions for treating particular memory deficits.  

The high affinity α4β2* nAChRs, form a pentamer in which the α4 and β2 stoichiometry varies (Figure 5). The ligand binding site is formed at the interface of the principal α4 and complementary β2 or α4 subunit, and any change in subunit complement impacts the number of binding sites. The different assemblies of the receptor have a major influence on various aspects of the receptor and its function, affecting its agonist and antagonist affinity, ion currents, conductance, allosterism, and desensitization kinetics.[70] The α4β2* nAChRs are located in the thalamus, cerebral cortex, substantia nigra, ventral tegmental area, and hippocampus.[71][72]

As mentioned above, α4β2* nAChRs are involved with different cognitive processes underlying attention, learning, and memory, and their numbers are significantly reduced in Alzheimer’s dementia. As a result, these receptors can serve as biomarkers of the progressive neurodegenerative changes accompanying cognitive deficits in AD. A recently developed α4β2* nAChR-selective radioligand 18F-flubatine along with PET scans of individuals with mild Alzheimer’s dementia, revealed loss of these receptors in areas crucial to the integrity of cognitive function at early stages of AD.[67] Specifically, reductions of α4β2* nAChRs in the hippocampus, fronto-temporal cortices, and basal forebrain accompanied impairments in episodic and working memory. These types of agents that index the loss of receptor and function could represent a marker to track the progression of AD.[67] 

Smoking upregulates these receptors in the brainstem and cerebellum, implicating subcortical α4β2* nAChRs in nicotine addiction.[73] The partial agonist of α4β2* nAChRs, varenicline, is used as an aid for smoking cessation. The recent specific and high quality radioligands of α4β2* nAChRs, introduced for PET scanning in humans offer the potential for faster and more accurate representation of the dynamics of the receptor in the brain. These compounds display rapid brain kinetics and high binding specificity that overcome the slower parameters of older analogs.[74] The radioligand 18F-AZAN is taken up robustly by the thalamus that is densely packed with α4β2* nAChRs, and also by other areas that contain modest levels of the receptor, such as the cortex, striatum, corpus callosum. Scans show that 18F-AZAN binding is demonstrably blocked in nicotine-exposed (smokers) and varenicline treated individuals, highlighting the areas of the brains bound by these α4β2* nAChRs agonists.[74] These tools, such as 18F-AZAN PET scans to image α4β2* nAChRs are fast and accurate, and are being employed to study neuropsychiatric and neurodegenerative diseases, such as schizophrenia and Alzheimer’s disease, and nicotine addiction.

The α7* nAChRs are enriched in regions of the brain that are involved with learning and memory.[75] These rapidly activating receptors are expressed in neuronal and non-neuronal cell types, including astrocytes, microglia, endothelial cells, suggesting important roles in immunity, inflammation and neuroprotection.[76][77][78] Activation of α7 nACHRs stimulates neurotransmitter release, significantly increases calcium permeability, neuronal excitability and other down-stream signaling events.[79][80] As a matter of note, the α7 nAChRs homopentamers are extremely permeable to calcium, and their calcium to sodium permeability is akin to glutamatergic N-methyl-D-aspartate (NMDA) receptors, the master calcium fluxers.[81] α7 nAChRs display relatively low affinity for ACh (EC50 ~ 180 mM) and  it is likely that they act in concert with other AChRs, both muscarinic and nicotinic.[82] Furthermore, their influence on post-synaptic targets is sensitive to the timing of their activation, a feature important for the plasticity of synaptic circuits.

The α7 nACHRs are highly expressed in regions that are important for long-term and spatial memory, and synaptic gating sites, - such as hippocampal CA1, CA3 and dentate gyrus, prefrontal and subcortical areas. α7 nACHRs participates in synaptic plasticity mediated by LTP and LTD, contributing to these processes essential for cognitive functioning.[75][83] The receptors have a broad distribution in the hippocampus, modulating network excitability and are expressed both pre- and post-synaptically on glutamatergic pyramidal neurons and GABA interneurons.[84] These receptors are associated with AD and their numbers are reduced in the brain, particularly the hippocampus of AD patients.[85] The α7 nACHRs additionally have high affinity for amyloid β peptide (Aβ) which is a a cardinal feature of AD. At low (picomolar to low nanomolar), Aβ peptide functions as an agonist and potentiates α7 nACHRs channel activity, whereas at higher (high nanomolar to low micromolar) it serves as a negative modulator and decreases the duration of receptor activation, disrupting ACh signal and circuit activity.[86] Therapeutic strategies aimed at promoting α7 nACHR activity to ameliorate cognitive impairment in AD is emerging as a promising target of intervention for these patients.

The α7 nACHRs have been studied for their role in reward and reinforcement, especially its relationship with dopaminergic signaling. In the ventral tegmental area (VTA) α7 nACHRs are located pre- and peri-synaptically on dopaminergic neurons and glutamatergic axon terminals.[87] They regulate neuronal excitability in the mesolimbic pathway responsible for reward and drug addiction, such as with nicotine and other drugs of abuse. Nicotine stimulates the release of dopamine in the nucleus accumbens via the mesolimbic pathway, mediating its reinforcing properties.

The α7 nACHRs are expressed widely in a variety of cells of the immune system, and their presence in and activation of microglia has been found to be anti-inflammatory. Furthermore, vagal nerve stimulation attenuates inflammation by potently inhibiting macrophage tumor necrosis factor (TNF), an effect mediated by α7 nACHRs in what is termed the ‘cholinergic anti-inflammatory pathway’ (CAP). [88] These receptors additionaly activate antiapoptotic signaling pathways that provide protection to neurons.[89]

The α7 nACHRs are of great therapeutic value for neurodegenerative and neurological diseases, especially one’s dependent on the hippocampus. It is challenging to develop drugs specific enough to obviate off-target effects, owing to α7 nACHRs wide distribution in neuronal and non-neuronal cells, coactivation with other receptors, activation and desensitization kinetics. Activation of nAChRs by ACh and other agents, e.g., nicotine, boosts memory and are being investigated for potential treatments for cognitive disorders related to diminished attention and learning, and memory.[90][91]

Acetylcholine Transporter[edit]

ACh is synthesized in the cytoplasm of cholinergic nerve terminals by the enzyme choline acetyltransferase (ChAT). Once synthesized, it is loaded into presynaptic vesicles by vesicular ACh transporter (VAChT) that belongs to the solute carrier family 18 member 3 class of transporters (SLC18A3). This loading process is dependent on the electrochemical gradient generated by proton ATPase,[92] and the active transport into vesicles at the presynaptic terminals is necessary for cholinergic neurotransmission, as ACh is a charged (cationic) molecule that cannot freely diffuse through membranes. In order to exert its effects, ACh must first be stored in synaptic vesicles prior to being secreted by vesicle fusion and exocytosis into the synaptic cleft.[26] Vesicles accumulate thousands of ACh molecules, representing discrete packages for quantal release. This quantal nature of neurotransmitter release was established by the pioneering work of Bernard Katz and his collogues in the 1950’s and 60’s, from work they did on ACh release from spinal motor neurons at the neuromuscular junction of frogs.[93] The VAChT is a membrane spanning protein with 12 transmembrane domains (TMD). It belongs to the same superfamily of transporters as other transporters such as vesicular monoamine transporters (VMAT), with which they share a high degree of sequence homology, especially in the TMDs.[92] The vesicular transport of ACh in striatal neurons is also influenced by the expression of the glutamate transporter in cholinergic neurons, a process of vesicular synergy. These transporters are indeed non-specific to some extent, a feature observed in other neurotransmitter systems as well, such as for dopamine and GABA.

The expression levels of VAChT is vulnerable to drugs and disease states such as AD. Specific agents that bind VAChT, i.e., analogs of vesamicol that can be imaged are being developed and could be of great utility in the diagnosis and monitoring of disease states linked to ACh dysfunction and depletion, such as AD, PD, and Downs syndrome.[94]

Anatomy and Pathways[edit]

Figure 2. Brain Acetylcholine Pathways. (Public domain image accessed on April 27, 2023)

The basal forebrain (BF) and the brainstem are the 2 main efferent cholinergic pathways (Figure 2.). The BF medial septal nucleus extends axon bundles to the hippocampus and entorhinal cortex, the vertical and horizontal diagonal bands of Broca (VDB/HDB), and to the olfactory cortex.  Cholinergic projections from the BF magnocellular nucleus (B nucleus) arise from large, dark (Nissl stain) neurons in the nucleus basalis of Meynert (nBM), and along with the substantia innominata (SI) represents a major source, supplying ACh to the rest of the cortex and amygdala.[95][96] These various trajectories extensively innervate the neocortex, basolateral amygdala, hippocampus, entorhinal cortex, and olfactory bulb.[97][98][99][100][101] As a consequence of their widespread distribution in the brain, cholinergic inputs are implicated in memory, learning, attention, sensory coding and cortical activation, and diseases that include Alzheimer's disease (AD), Parkinson's disease (PD), drug abuse, autism, schizophrenia, and attention-deficit hyperactivity disorder ADHD.[102][99][100][4] The major nuclei, nBM/SI contribute significantly and along with the rest of BF nuclei comprise well over 500,000 neurons in humans. They contain between 200,000 to 230,000 cholinergic neurons per hemisphere in humans, and make up the majority, ~90% of the cell types in the nBM/SI.[103][4]

The brainstem pedunculopontine and dorsolateral pontine tegmental nucleus cholinergic systems send projections mostly to the basal ganglia, thalamus, and basal forebrain regions.[104] This cholinergic system has been implicated for its role in the sleep-wake cycle and some work suggests that it may play a role in controlling balance and gait.[104] For the purposes of this article the focus will be on the basal forebrain cholinergic system.

Neuronal tracing techniques have identified specific neuronal networks between the basal forebrain (BF) cholinergic neurons and the sensory, motor, prefrontal cortices, implicating them in cortical function.[100] Retrograde tracing and optogenetic stimulation models suggest that the caudal BF and magnocelleular B nucleus are less specific in their connections to the sensory cortex compared to the vertical and horizontal diagonal bands of Broca.[105][100] The VDB/HDB also maintain reciprocal connections with prelimbic/infralimbic (PL/IL) regions of the medial prefrontal cortex (mPFC). Stimulation of the HDB in rodents elicits muscarinic receptor mediated sensory (whisker) response in the primary somatosensory cortex (S1), whereas nicotinic ACh receptors are implicated in the inhibition of the same sensory response by HDB in the mPFC.[100] This points to a more specific rather than diffuse control of cortical activity by cholinergic networks.

The organized pathways referred to above constitute the bulk of cholinergic projections, and just as with other major neurotransmitter systems, confers heterogeneity by extending axons from different subpopulations to different sites and binding to different receptors. Crucially, local interneurons, such as in the striatum, represent a second major source of ACh, with high densities - higher than extra-striatal sources - although there is considerable overlap between the two.[14] Striatal cholinergic interneurons (CINs) integrate with dopaminergic signaling in reward and motor functions. The 2 mostly separate sources of ACh subserve different functions with distinct overtones. In this regard, silencing nucleus accumbens CINs elicits depression-like states, while extra-striatal anti-cholinergic effects are mainly anti-depressive.[106] These and other reports suggest that cholinergic activity has an important role in regulating depression, mood, and motivational states.  

It is notable that the even though the neocortex receives significant cholinergic projections from the nBM/SI, the density of innervation between the cortical regions differs, and this concomitantly results in differences in ACh release. The core limbic structures such as the hippocampus and amygdala receive a higher density of cholinergic inputs in humans.[107] ACh axons are also clustered in frontal cortical regions as compared to other highly studied animal models, and these clusters could be relevant for plasticity. The interspecies differences in innervation patterns should be kept in mind while interpreting reports on the cholinergic system, as these differences are consequential for the physiological and functional impact, and modulation by this neurotransmitter.

There is great heterogeneity in the neurons of the BF, with intermingled cholinergic, GABAergic, and glutamatergic populations.[108] There remains a significant degree of interspecies differences in the breadth and phenotype of this ‘cholinergic’ nucleus, and caution is recommended when reviewing the literature spanning rodents to non-human primates, and humans. Albeit it, the basal forebrain region is largely the nexus of ACh supply to the central nervous system.[95]  

Based on their location in the BF, cholinergic neurons map topographically - ventral to dorsal – to distinct medial prefrontal cortical (mPFC) regions and to different cortical layers. Specifically, ascending BF cholinergic efferents follow four routes to innervate the mPFC, with a ventral to dorsal distribution of fibers depending on their specific location along the rostro-caudal extent of the BF.[99] The regional bias in cholinergic input to distinct mPFC regions could be crucial for cognitive function and information processing. Studies have detailed the role of cholinergic afferents in altering the temporal dynamics resulting in decorrelation of cortical spike trains that is essential for enhancing information processing during attentional tasks. Primary sensory cortices process modality-specific information, and their physiological properties are under dynamic control of subcortical cholinergic and other neuromodulators.[109] Cholinergic circuits, for example in the visual cortex, facilitate inhibition of parvalbumin (PV)-expressing inhibitory neurons by somatostatin (SOM), culminating in disinhibition and decorrelation of pyramidal neurons, which is purported to enhance signal processing and is advantageous for visual processing in this local circuit.[110] These kinds of studies define how the diffuse cholinergic drive is selectively transformed by ACh-sensitive neuronal populations in order to drive local, specialized microcircuits underlying discrete cortical functions.[111]

Detailed reconstruction of the whole mouse brain deploying genetically labeled cholinergic neurons, using a Cre-dependent fluorescent reporter line and tomography-based imaging, has revealed discrete subgroups with distinct patterns of projections. These cholinergic neurons can be classified as cortical VIP-containing neurons, projection neurons, and brainstem motor neurons.[101] The comprehensive atlas of the basal forebrain cholinergic projectome of ACh neurons illustrates that individual cholinergic neurons innervate several functionally interconnected regions, Furthermore, in contrast, projections of neighboring neurons can be dissimilar, across various cortical and sub-cortical regions. The cortical cholinergic cells, most ~90% of which contain VIP have discrete laminar distribution and elaborate dendrites in different layers, modulating the activity of cortical circuits to influence output.[101]

The basal forebrain in humans, likewise, as determined by post-mortem cytoarchitectonic studies and functional imaging has revealed subregions that project to different cortical regions and layers. These distinctions in ACh neuronal subpopulations and their distinct trajectories could feasibly impact information processing and be crucial for distinct attentional states and cognitive functions subserved by those target sites.[102]

The medial septum/diagonal band of Broca (MSDB) is the main source of ACh for the hippocampus and is essential for rhythmogenesis. ACh from the MSDB has been observed to act on the hippocampus via 2 distinct pathways to promote encoding novel information either directly or indirectly.[112] The direct septo-hippocampal pathway stimulates inhibitory interneurons in the hippocampus that suppress the activity of the pyramidal neurons. Whilst the indirect pathway operates by activating local MSDB non-cholinergic relay neurons that function to also inhibit the pyramidal neurons and coordinate the timing of the oscillations underlying memory encoding.[112]

Review of decades of studies on the cortical cholinergic system that employ different methodologies, target different cortical areas, and the differences in distribution of fibers within the brain in species ranging from rodents to primates, and humans suggest a canonical cortical model system does not appear to exist for the cholinergic system.[4] Throughout, studies have been combined to proffer a unified model system of cholinergic modulation of cortical function. It is therefore incumbent upon the reader to be aware that functionally equivalent cases may not necessarily have the equivalent anatomical substrate - functionally equivalent circuits are derived from unique anatomical circuits in different species. [4]

ACh Function[edit]

Ever since its discovery, ACh has been recognized as a significant modulator of cognitive processes, especially memory, and the dysregulation of the cholinergic system is evident in pathologies such as dementia and Alzheimer’s disease (AD).[113][114] The extent of cholinergic impairment across the neocortex is associated significantly with the extent of functional memory deficits and severity in AD dementia.[115]

Other pathological conditions associated with low or dysfunctional ACh, such as dementia with Lewy bodies, Korsakoff’s syndrome, cerebral infarction resulting from rupture of anterior communicating artery also have an adverse impact on memory and other cognitive states.[116][117][118][119]

Arousal and Attention[edit]

Based on decades of research on animal models, the basal forebrain (BF) cholinergic system has been characterized as tonic and diffuse, with extracellular levels that change slowly (over minutes), a scenario consistent with volume transmission (VT). As a result, traditional models of the small number of basal forebrain cholinergic neurons with their varied trajectories were deemed to act globally to modulate cortical excitability. ACh is released from the varicosities along the length of its axons, in line with VT rather than spatially restricted synaptic transmission.[120] As a result, cholinergic signaling was associated with general states of arousal and alertness. Recent advances in cell labelling, imaging techniques, and electrophysiology, have brought into sharper focus the spatiotemporal firing characteristics of the cholinergic neurons,[121] especially in non-human primate models.[122]

ACh is a potent neuromodulator, acting to facilitate or suppress cortical activity. Its global and now clearly defined discrete projections, enable versatile and hierarchical modulation of the activity of different cortical areas and layers.

New insights obtained from recent evidence have reconceptualized the cholinergic neurons as actively engaged, providing inhibitory or excitatory synaptic inputs to distinct cortical circuits over different time scales associated with different cognitive and behavioral operations, a scenario more indicative of phasic and wired, rather than volume neurotransmission.[123][124] Refined pharmacological and electrophysiological techniques have demonstrated spatially restricted, phasic ACh release that is suited to and subserves attention and sensory processing in addition to the widespread tonic release in the cortex that is concerned with general arousal and brain state-dependent functions.[125] In line with this, cortical cholinergic transients - spatially discrete fast ACh release - have been demonstrated to elicit muscarinic-related high-frequency oscillations that outlast the transients and persist throughout the duration of an attentional task. Cues that evoke cholinergic transients in the prefrontal cortex (PFC) are superimposed over the slower, spatially diffuse, tonic activity, demonstrating the regulation of cholinergic neurotransmission at multiple levels.[126] The underlying neural circuitry effectively links the phasic firing of cholinergic neurons to specific attentional and other deterministic, cognitive and behavioral states, whereas slow, tonic  discharges are purportedly linked to general arousal.[124] The local and phasic ACh release at specific cells groups, and the broad tonic network-coordinating cortical activity may represent inputs from functionally and spatially distinct subsets of BF cholinergic neurons, tasked with different aspects of information processing.[125][127] 

The BF projections to different cortical areas have been extensively mapped by retrograde markers and imaging techniques. Furthermore, their activity has been recorded and probed using electrophysiological protocols, electroencephalograms (EEG), and microdialysis. BF cholinergic neurons are neuromodulatory, providing broad stimulation to neocortical areas and facilitate the functioning of non-cholinergic inputs. Stimulation of subsets of cholinergic BF neurons elicits broad and discrete ACh release in somatosensory, motor, and visual cortices.[128] In this regard, BF cholinergic efferents are topographically organized into clusters that overlap depending on their function and the extent of their cortical innervation patterns. For instance, in the primary somatosensory cortex (S1), there is minimal overlap of cholinergic inputs to sites representing different parts of the body (whisker vs hindlimb). Although, BF cholinergic neuron clusters overlap in S1 and analogous primary motor M1 regions. Similarly, the primary visual cortex receives broad cholinergic input that potentiates visual processing and regulates visual attention and plasticity. The anterior horizontal band of Broca (HB) and substantia innominata (SI) tend to innervate the primary visual cortex (V1), on the other hand the secondary visual cortex (V2) receives inputs from all areas of the BF.[121] The study established some organization but did not recapitulate the retinotopic organization of the visual areas that are themselves functionally organized. This kind of evidence implies that discrete cortical areas can receive cholinergic inputs from different levels of BF subregions, and that different BF cholinergic subregions generate broad projections across the cortex. It is well recognized that there is a distinct organization of BF-cortical cholinergic system that seems to underlie the two forms of signaling, global and specific, and that basalo-cortical projections modulate cortical processing at different hierarchical levels in order to influence their activity.

Specific BF cholinergic neuronal populations are dynamically recruited to modulate cortico-cortical connections during different stages of behavioral tasks. Neural oscillations along with temporally coordinated inputs promote the transmission and integration of information underlying behavior. Neuronal interactions are regulated and strengthened by synchronization that is dependent on gamma-band (30 -100 Hz) oscillations and gamma coherence.[129] The periodicity of these oscillations is indicative of competing excitatory and inhibitory influence on local neural circuits. There is a distinct spatial distribution of gamma coherence between basalo-cortical and cortico-cortical sites during different phases of the behavior.[130] BF cholinergic inputs modulate the activity of these cortical circuits. Specific BF ACh neurons are activated during different stages of a visual discrimination task in this particular animal model and serves to coordinate the activity of cortical circuits essential for task performance and cognition.

Basal forebrain cholinergic inputs to the cortex contribute significantly to arousal, attention and learning. These afferents modify the synchronicity of neural circuits, altering and suppressing ongoing cortical activity. The resulting desynchronization boosts the signal-to-noise ratio, reducing the background spontaneous activity, which benefits the coding of relevant sensory information and concomitantly increases arousal and attention.[131] The modulation by BF cholinergic cortical afferents have been observed widely, including in the somatosensory and visual cortices.[110][131] These inputs simultaneously enhance sensory processing while dampening intrinsic cortical activity, thus playing an active role in influencing the dynamics of neural activity.

In the striatum, cholinergic afferents are involved in behavioral flexibility. The ability to adapt in response to changing environmental demands contributes to corticostriatal plasticity and is deemed important for shifts in strategy to mount an appropriate response. Cholinergic interneurons in the dorsomedial striatum facilitate, via an mAChR sensitive mechanism, the acquisition of new behaviors in response to changing environmental conditions and establishes the crucial role of these interneurons in cognitive flexibility.[132][133] Cholinergic neurons that project from the BF to the hippocampus, basolateral amygdala, and the posterior parietal cortex have also been shown to contribute to cognitive flexibility when learning to establish new behaviors.[132] Dysfunction in this ability is observed in pathological disorders from autism and AD to ADHD.

Cholinergic signaling that is essential for improved cognition, and learning and memory, can be deleterious at high levels. Increased ACh heightens sensitivity to stress and symptoms related to anxiety and depression. It is possible that elevated cholinergic signals lead to encoding of stressful events, and therefore balanced ACh levels are considered optimal for appropriate learning, mood regulation and reactivity to stress.[134]

Volume or wired, synaptic, ACh release is implicated in the transition between states such as arousal, attention, memory, and sleep-wake cycles. Certain states require a particular mode of cholinergic signaling over the other, however it is not yet clear whether they represent dominant or complementary modes of cholinergic neurotransmission. Investigations continue to clarify these issues. However, it is abundantly clear that cholinergic input markedly modulates cortical function, and disruption of this system leads to dysfunction and pathological conditions.

Memory[edit]

Cholinergic neurons project widely to different areas of the hippocampus and play an important role in the formation of episodic, semantic memory, and the encoding and consolidation of memory.

Memory has long been considered to be reactive, i.e., responding to external aspects of the environment, such as the emotions it evokes; the abstractions either, semantic or perceptual; or the observations of anatomical correlates, such as hippocampal neural plasticity. However, internal, sustained neural states, have been demonstrated to play an equally important role in determining the fate of a memory - its encoding, consolidation, and retrieval. ACh is fundamental to memory processes, with its dynamic shifts in time scales and import for enduring neural states.[135] In fact, the hippocampal cholinergic activity biases the bottom-up, externally biased mode, and the top-down processing relevant for the internal cognitive bias. The septo-hippocampal cholinergic afferents are integral to confining the encoding and retrieval of memory into separate functions by adaptively influencing the timing and sequences of these operations, thereby reducing interference during the learning process.[136]

Over long timescales, ACh signaling enhances hippocampal synaptic plasticity, including long-term potentiation (LTP), and long-term and short-term depression (LTD, STD).[137][138][139] Hippocampus is the locus for the salient aspects of memory, whereby the representation of the current, novel experience is constrained from eclipsing memories of similar, previously encountered events. This process of ‘representative transformation’ is achieved through pattern separation, which transpires with high ACh levels in the dentate gyrus (DG) and is important for distinguishing between similar memories.[140][141][142][143][144] Inputs from the entorhinal cortex (EC) that reflect similar events are transmitted, via the perforant pathway to the DG, where they are organized and recoded into separately ordered experiences. This information follows a one-way trajectory and is parsed through the CA3 and CA1 Schaffer collaterals. Long-term potentiation (LTP), a form of synaptic plasticity strengthens connections between coactivated neurons, laying down an engram, or memory trace, indexing the experience for future retrieval.[142][143][144] When encountering new experiences, low ACh levels facilitate the access of the dormant memories associated to similar past events, through a separate process of pattern completion.[13][140] In support of this, blockade of central muscarinic receptors by the antagonist scopolamine, impairs memory formation, especially with competing events, i.e., proactive interference, while sparing the recall and retrieval of stored experiences.[145] This and similar evidence supports the role of ACh in associative memory and the underlying  neural dynamics, especially in the context of encoding new experiences.[146]

Cholinergic signaling has differential effects on the EC, which serves as an intermediary between the neocortex and the hippocampus, funneling information between the two. The EC receives profuse cholinergic inputs from the BF, specifically the superficial layer II and deep layer V, the precise layers that gate hippocampal input and output, respectively.[147] Superficial layers of the EC receive convergent inputs from the entire cortical mantle related to extrinsic, sensory signals. Cholinergic afferents modulate and synchronize the activity of these superficial cortical inputs and transmit the information via the perforant pathway to the hippocampal formation, areas that are central to encoding information.[148] The superficial layers are more active during waking. Hippocampal areas also receive cholinergic inputs and in turn projects to deeper layers of the EC that reciprocally project back to the neocortex for memory consolidation. Deeper EC layers are more active during quiescent, sleep periods, during a time when memory is strengthened.[149][150] The EC plays a key role in cognition, and this is underscored by the pathological changes observed in the superficial layers in neurodegenerative conditions such as AD.

Cholinergic afferents to the hippocampus are proposed to enhance the functional circuitry responsible for encoding novel information. The anatomically and functionally distinct direct and indirect afferents from the medial septum/diagonal band of Broca (MSDB) are key to modulating hippocampal rhythmogenesis. MSDB cholinergic input to the hippocampus promote theta (3 – 6 Hz) oscillations - activity during exploration, novelty seeking, and encoding - and synchronize the activity of CA3 pyramidal neurons.[112] The direct septo-hippocampal pathway promotes encoding by activating inhibitory interneurons that drive the suppression of CA3 principal neurons.[151][152] The indirect pathway relies on intraseptal ACh activation of non-cholinergic, putative parvalbumain (PV+) neurons, that in turn enhance the theta rhythm and synchronicity of the CA3 pyramidal neurons, an effect most likely mediated by metabotropic receptors.[112] Thus, ACh acts synergistically, deploying separate pathways to actively suppress CA3 pyramidal cells and induce theta oscillations in service of information encoding. The direct inhibition confirms previous models that proposed the quick (seconds) inhibition of CA3 autoassociative network being essential for encoding new information.[151]

Computational models of the cholinergic BF system and its modulation of neuronal microcircuits at the cellular and synaptic level are extremely useful and confirm decades worth of experimental data.[153] These data-driven models can provide an invaluable aid for integrating experimental detail at cellular and neural circuit levels into network and system-level frameworks to advance our understanding of nervous system function at all levels. These frameworks incorporate and integrate phenomenological models of distinct and diverse neocortical circuitry in order to identify their emergent properties. Data-driven frameworks not only recapitulate decades of detailed work on cholinergic modulation of different cell types at different neurons in different regions and species but offer ways to refine current hypothesis and elucidate mechanisms of neuromodulation that would apply to other neural information processing systems as well.[153]

Neurodegenerative Diseases[edit]

Alzheimer’s Disease (AD)[edit]

Alzheimer’s disease (AD) is the leading form of dementia, accounting for a significant percentage of all dementia cases, and its prevalence is projected to keep rising worldwide, especially with an ever-aging population. Currently in the US, 6.7% of adults over the age of 65%, 73% of them over 75 years, live with AD dementia.[154] AD is neurodegenerative and is characterized by progressive cognitive decline associated with loss of cholinergic function.[116] Concurrently, the decline in basal forebrain (BF) cholinergic system is seen in early AD and at-risk individuals.[116][155][118] Episodic memory, the conscious ability to retrieve previous life experiences is severely compromised in AD and represents an early symptom of the disease.[156] Atrophy in the BF is correlated with increased cortical amyloid burden, a pathological trademark of AD, whereas the decline in hippocampal volume is more in tune with diagnosing AD and mild to severe cases of cognitive impairment.[157] Structural changes and possibly functional connectivity in the nucleus basalis of Meynert (nBM) during the prodromal phase of individuals with mild cognitive impairments are positively correlated with changes in the thickness of the temporal lobe and the volume of the amygdala, more so in woman.[158]

In 1980's it was evident that the the etiology of AD involved progressive cortical, limbic, and BF cholinergic impairment contributing to the loss of cognitive function and age-related memory deficits.[159] The 'cholinergic hypothesis’ was convincingly supported as anticholinergic agents demonstrably induced cognitive dysfunction, whereas cognitive function was bolstered with cholinesterase inhibitors (AChEIs) that hamper the deactivation of ACh.[160] AChEIs function to elevate the availability of ACh at the synapse for neurotransmission and have proven to be effective in improving AD dementia. They represent the earliest and most widely prescribed class of drugs clinically approved in the treatment of AD symptom, thus validating the ‘cholinergic hypothesis' of cognitive dysfunction tied to AD.[161]

The decades old ‘cholinergic hypothesis’ of AD neuropathology is supported by compelling evidence for reduced activity of the rate-limiting enzyme in ACh synthesis, choline acetyltransferase (ChAT), reduced number of cholinergic neurons in the nBM, and reduced levels of nAChRs, more so than mAChRs.[162][163][116][164][165] The view receives wide support, as in attempts to increase ACh levels, natural and synthetic AChEIs with reversible and pseudo-irreversible binding profiles such as donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), reduce the activity of the catabolizing enzyme cholinesterase, with differential effects and are effectively deployed in treating AD.[33][166][35][167][168] These reports concluded, based on available clinical data that galantamine was more efficacious in addressing all symptoms of AD and has more utility in disease intervention.[166] In addition a recent literature review concluded that donepezil (10 mg/day) was effective in moderating the cognitive deficits and improving the global status of AD patients, with little impact on behavior, and that it also decreased the mortality rate in patients with mild to moderate AD.[169] These AChEIs can be used in combination with the uncompetitive NMDA receptor antagonist memantine (Namenda), a drug that prevents the pathological influx of Ca2+ underlying glutamate excitotoxicity. Over activation of glutamate receptors leads to ACh neuronal loss in AD.[170] The pathophysiology of AD is incredibly complex and there are symptomatic differences between individuals that characterize this disorder. In light of this it is unlikely that a single class of drugs, such as AChEIs are sufficient to treat AD and other dementia. Treatments that combine these drugs with other agents including ACh precursors, NMDA receptor antagonists, and antioxidants is garnering much interest in treating these complicated neurodegenerative and adult-onset dementia.[171]

Moreover, amyloid β peptide-42 (Aβ-42), the predominant amyloid found in humans, starts to accumulate early on in vulnerable neuronal populations, preceding the onset of full-blown AD.[172] This amyloid peptide piles up inside BF cholinergic neurons even at young ages and proceeds to pathological states in dementia and AD.[150] Neurofibrillary degeneration of BF leads to loss of forebrain cholinergic neurons and compromises the widespread cholinergic input to the cortical structures. Assessment in humans with early onset, asymptomatic AD, point to the prominence of impaired presynaptic basal forebrain nBM cholinergic neurons and their cortico-limbic projecting axons. The pre—and post-synaptic ACh receptors also undergo profound changes, for instance post-synaptic cortical nicotinic receptor loss is observed in AD.[173][65][174] The preferential accumulation of Aβ in the hippocampus and neocortex, regions that are enriched with α4β2* and α7* nAChRs and the high affinity (picomolar to nanomolar) interaction between Aβ and these receptors could significantly impact synaptic transmission and plasticity, including with negative consequences on operations of neural networks.[175][176] Drugs that selectively target these nAChRs, with the desired pharmacological profiles are being designed as interventional tools for the treatment of mild to moderate cognitive impairment and AD.

In addition to the widespread disruption of cholinergic neurons, alterations in presynaptic molecules such as loss of the synthetic enzyme ChAT and transporter VAChT activity has been linked to the cognitive and memory impairments. As a result, dysfunction at pre-synaptic cholinergic neurons and not post-synaptic sites provide suitable targets for imaging and diagnosing AD.[177] PET imaging of various aspects of ACh neurotransmission offer utility in AD, with respect to diagnosis, staging, disease progression and monitoring, and assessment of therapies for the condition. The rapid evolution of selective radioligands has allowed for imaging ACh receptors, transporters and enzymes, and microglia. This enables real-time visualization of pathological changes occurring along with cognitive decline and concomitant disease progression.[178]

Recent exploration of human neural stem cells is proving promising to ameliorate not just the symptoms of, but improve the complex cognitive and physical deficits of AD.[179] ChAT-expressing stem cells transplanted into AD animal model systems have been observed to differentiate into neurons and astrocytes that produce ChAT, release ACh, and reduce Aβ deposits. They also restore growth factors and lead to the proliferation of stem cells in the host, improving the cognitive and physical deficits.[179] Therapeutic strategies employing neural stem cells to restore cognitive and neurobehavioral function represents a more stable and lasting approach, in lieu of chemical interventions with drugs that transiently ameliorate certain symptoms of AD.

Other studies are investigating the modulatory role of the endogenous cannabinoid system and its receptors in regulating cholinergic mAChRs associated with AD, and could prove to be promising targets for treatment.[180]

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