acetylcholinesterase

Overview

Acetylcholinesterase (AChE; EC 3.1.1.7) is a serine hydrolase enzyme responsible for the rapid hydrolysis of the neurotransmitter acetylcholine (ACh) at cholinergic synapses, terminating synaptic transmission in both the central and peripheral nervous systems. By cleaving acetylcholine into choline and acetate, AChE regulates the duration and intensity of cholinergic signaling, making it indispensable for normal neuromuscular function, autonomic regulation, and cognitive processes including learning and memory. AChE is expressed across diverse tissue types — most prominently in neurons, erythrocytes, and neuromuscular junctions — and its activity in red blood cells and plasma serves as a standard clinical biomarker of neurophysiological health. Inhibition of AChE increases synaptic acetylcholine levels, a mechanism exploited therapeutically in Alzheimer's disease (AD) management via drugs such as donepezil. Conversely, toxic suppression of AChE by organophosphate compounds — including pesticides and chemical warfare agents — underlies cholinergic toxidrome, a potentially fatal syndrome characterized by excessive glandular secretion, bronchospasm, and seizures.

Beyond its canonical synaptic role, AChE participates in non-classical functions including cell adhesion, neurite outgrowth, and responses to cellular stress such as hypoxia and oxidative stress. Closely related to butyrylcholinesterase (BChE), which also hydrolyzes acetylcholine and other esters with broader substrate specificity, AChE remains the primary pharmacological target in Alzheimer's disease research. The co-occurrence of AChE dysregulation with metabolic conditions including diabetes and comorbidities such as oxidative stress has expanded its relevance beyond pure neuropharmacology into integrative biomedical research.

Focus of Latest Publications

Recent publications on acetylcholinesterase have focused heavily on its role as a therapeutic target in Alzheimer’s disease and related neurodegenerative settings, with many studies centered on the discovery of new cholinesterase inhibitors. Several reports described synthetic small molecules with dual or multitarget activity, including flavonoid-fused aminoquinolines, quinazolinone-chalcone hybrids, chiral anthranilic diamides, thieno[3,2-d]pyrimidine-phenolic Mannich base hybrids, coumarin-based derivatives, benzothiazole-linked oxadiazoles, and optimized hydrazide-hydrazone indole congeners. Across these studies, acetylcholinesterase inhibition was commonly paired with butyrylcholinesterase, BACE1, MAO-B, or GSK-3β inhibition, and the most active compounds often showed nanomolar or low-micromolar potency. Molecular docking, molecular dynamics simulations, MM-GBSA calculations, and ADMET analyses were frequently used to support the experimental findings and to prioritize lead candidates.

Natural products and plant extracts were also repeatedly evaluated for acetylcholinesterase inhibition. Methanolic extracts of Salvia heldreichiana, Bellis annua, Epimedium pubigerum, olive leaves, and chlorophyll/carotenoid-rich fruit tree leaf extracts all showed measurable AChE inhibitory activity, usually alongside antioxidant and other enzyme-inhibitory effects. In these studies, phytochemical profiling identified Phenolic Acids, flavonoids, and related constituents such as rosmarinic acid, chrysin, hyperoside, and chlorogenic acid as likely contributors to bioactivity. Docking analyses were used to connect these compounds with acetylcholinesterase binding, supporting the broader interest in plant-derived scaffolds as sources of neuroactive agents.

Acetylcholinesterase was also investigated in studies aimed at neuroprotection and disease modification beyond direct enzyme inhibition. Canagliflozin, described as a dual inhibitor of SGLT2 and acetylcholinesterase, was tested in a streptozotocin-induced Alzheimer’s disease model and was reported to improve hippocampal dendrite morphology without significant changes in dendritic spine density. Trans-anethole and lawsone were evaluated in animal models of cognitive impairment, where acetylcholinesterase activity was measured alongside oxidative stress and inflammatory markers; both compounds were reported to reduce AChE activity and improve neurobehavioral or histopathological outcomes. empagliflozin and dapagliflozin were also examined in silico and in vivo, with docking suggesting interactions with AChE and other targets relevant to cognitive dysfunction.

Beyond therapy development, acetylcholinesterase has been used as a biomarker and analytical target. A chemiluminescent AChE-responsive probe was developed for acute ischemic stroke imaging, based on the observation that AChE is upregulated under anaerobic stress; the probe enabled sensitive detection and in situ visualization of hypoxic brain injury in a mouse model. Another study created a reusable interface-decoupled organic photoelectrochemical transistor biosensor for AChE activity and chlorpyrifos detection, demonstrating sensitive monitoring of enzyme activity and inhibition. In organophosphate poisoning research, brain-targeted HI-6-loaded metal-organic framework nanoparticles were designed to improve central nervous system AChE reactivation, with intranasal delivery showing enhanced reactivation in a mouse model.

Key Publications

• NEWJul RANQSAR: a standalone open-source application for reproducible machine learning-based QSAR analysis. (Journal of computer-aided molecular design, 2026, PMID 42390765): "We showcase the usefulness of RANQSAR using acetylcholinesterase inhibitors as a model study case and demonstrate that the platform allows one to develop a reproducible regression QSAR model and carry out a comparative benchmarking."
• NEWJun The effect of canagliflozin on hippocampal dendrite morphology in a model of Alzheimer's disease induced by intracerebroventricular injection of streptozotocin. (Brain structure & function, 2026, PMID 42289507): "Canagliflozin, a novel option for DM treatment, is a dual inhibitor of sodium glucose co-transporter type 2 (SGLT2) and acetylcholinesterase."
• Jun Evaluation of the Phytochemical Composition, Antioxidant Activity, and Enzyme Inhibitory Potential of Salvia heldreichiana Within the Framework of Molecular Docking and CAVER Tunnel Analysis. (ChemistryOpen, 2026, PMID 42220228): "The methanolic extract also displayed measurable inhibitory activity against acetylcholinesterase and tyrosinase, suggesting potential relevance for neuroprotective and dermatological applications."
• May Promising Flavonoid-Fused Aminoquinolines as Synthetic Alzheimer's Disease Models: Design, Synthesis, Anticholinesterase Activity, ADMET and Molecular Docking. (Chembiochem : a European journal of chemical biology, 2026, PMID 42179001): "...were evaluated for their AChE and BChE inhibitory activity and subjected to molecular docking studies."
• Jun Bismuth hybrid halide with dual inhibition against α-amylase and acetylcholinesterase probed by structural, vibrational, and theoretical analysis. (Journal of materials chemistry. B, 2026, PMID 42171151): "Most significantly, enzymatic inhibition assays demonstrated the compound's exceptional dual bioactivity. It exhibited potent inhibition against acetylcholinesterase (AChE, IC50 = 1.96 ± 0.1 mM) and α-amylase (IC50 = 0.27 ± 0.014 mM),"
• May Neuroprotective effects of trans-anethole on AlCl₃-induced memory impairment: targeting AChE, oxidative stress, and NLRP3 inflammasome: a promising approach for neurodegeneration prevention. (Metabolic brain disease, 2026, PMID 42154340): "Neuroprotective effects were evaluated by analyzing acetylcholinesterase (AChE) activity, oxidative stress markers (catalase, glutathione, and malondialdehyde levels), and neuroinflammatory mediators (NLRP3 inflammasome, Interleukin-1β, and TNF-α) in AlCl₃-exposed rats."
• May Solvent-free synthesis of quinazolinone-chalcone hybrids and their evaluation as dual inhibitors of AChE and BuChE for alzheimer's disease. (Die Naturwissenschaften, 2026, PMID 42149153): "In vitro evaluation of the five top-ranked compounds (3e, 3f, 5, 3i, and 3 h) for AChE and BuChE inhibition relative to donepezil."
• May Chemiluminescent Probe Enables Enhanced Visualization of Acute Ischemic Stroke via Acetylcholinesterase Activation. (Analytical chemistry, 2026, PMID 42118815): "Acetylcholinesterase (AChE), markedly upregulated under anaerobic stress, has emerged as a promising hypoxia biomarker; however, its potential for AIS visualization remains unexplored."
• May Multitarget pharmacological effects of Lawsone in mitigating Alzheimer's disease. (European journal of pharmacology, 2026, PMID 42105996): "Computational evaluation showed strong binding to NF-κB, c-JNK, acetylcholinestrase (AChE), butyrylcholinestrase (BuChE) and TNF-α, supporting its multi-target potential."
• Jun Reusable interface-decoupled organic photoelectrochemical transistor biosensing for acetylcholinesterase activity and its inhibitor detection. (The Analyst, 2026, PMID 42093401): "the incident light transmission can be modulated in response to acetylcholinesterase (AChE) activity and its inhibition by chlorpyrifos (CPF)."