Targeting acetylcholinesterase and butyrylcholinesterase in dementia

Lane, Roger M.; Potkin, Steven G.; Enz, Albert

doi:10.1017/s1461145705005833

Cited by 654Cholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Targeting acetylcholinesterase and butyrylcholinesterase in dementia

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Lane, Roger M., Potkin, Steven G., Enz, Albert·2005·The International Journal of Neuropsychopharmacology

DOI 10.1017/s1461145705005833

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Abstract

The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.

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Both acetylcholinesterase and butyrylcholinesterase are useful therapeutic targets for the treatment of Alzheimer's disease.
“Consequently, both enzymes are useful therapeutic targets for the treatment of AD [16].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [16]

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Authors: Lane, R. M., Potkin, S. G., & Enz, A.
Affiliations: Novartis (United States) (US)
University of California, Irvine (US)
Novartis (Switzerland) (CH)
Corresponding author: Potkin, Steven G.
ORCID: Lane, Roger M.
Potkin, Steven G.
Venue: The International Journal of Neuropsychopharmacology
Publisher: Oxford University Press (OUP)
Published: 2005-08-05
Volume: 9
Issue: 01
Pages: 101
ISSN: 1461-1457 (ISSN-L)
1469-5111
DOI: 10.1017/s1461145705005833
OpenAlex: W2158603760
Cited by: 654
References: 206
Citations by year: 2026: 43 · 2025: 37 · 2024: 47 · 2023: 40 · 2022: 54 · 2021: 45 · 2020: 47 · 2019: 46 · 2018: 41 · 2017: 26 · 2016: 36 · 2015: 25 · 2014: 30 · 2013: 20 · 2012: 25
FWCI: 1.62
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The International Journal of Neuropsychopharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: acetylcholinesterase, butyrylcholinesterase, cholinesterase inhibitors, Alzheimer's disease, dementia, cholinergic hypothesis, acetylcholine, frontal cortex, tau phosphorylation, amyloid hypothesis, disease progression, neuropsychiatric symptoms, enzyme substrate specificity
MeSH terms: Acetylcholinesterase, Alzheimer Disease, Animals, Butyrylcholinesterase, Central Nervous System, Cerebrovascular Circulation, Cholinergic Fibers, Cholinesterase Inhibitors, Dementia, Gene Expression Regulation, Humans, Isoenzymes, Neuroglia, Polymorphism, Genetic, Drug Delivery Systems

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Targeting acetylcholinesterase and butyrylcholinesterase in dementia

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