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Biomolecules
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Cholinesterases in Alzheimer's Disease
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Cholinesterases in Alzheimer's Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-inspired Molecules".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 29763

Special Issue Editor

Prof. Dr. Sultan Darvesh

E-Mail Website
Guest Editor
Departments of Medicine (Neurology and Geriatric Medicine) and Medical Neuroscience, Dalhousie University, Halifax, NS B3H 4R2, Canada
Interests: Alzheimer's disease; diagnostic and therapeutic agents for dementia; acetylcholinesterase; butyrylcholinesterase; neurodegenerative disease; neuroimaging; medicinal chemistry; enzyme kinetics; cognitive neurology; brain banking
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders that causes dementia. This condition was described over a century ago and, despite all the subsequent research, the cause of AD remains unknown. In this condition there is loss of various neurotransmitter systems, the most severely affected being the cholinergic system. It has been observed that the two enzymes, acetylcholinesterase and butyrylcholinesterase, that metabolize the neurotransmitter acetylcholine, are affected in AD where the level of brain acetylcholinesterase has been shown to be decreased while that of butyrylcholinesterase either increased or remained the same. Cholinesterase inhibitors are used to treat symptoms of AD. Cholinesterases become associated with the neuropathological hallmarks of AD, namely, tau neurofibrillary tangles and β-amyloid plaques. The reason for this association is unclear. Cholinesterases, in addition to their enzymatic properties, are known to have other “non-classical” functions including adhesion functions, interaction with other macromolecules and involvement in metabolic and inflammatory disorders.

In this special issue of Biomolecules called “Cholinesterases in Alzheimer’s Disease” we would like to explore the various aspects of cholinesterases, including both enzymatic and non-enzymatic properties, to try and consolidate available information and ascertain how this focus may inform future research towards an understanding of the underlying causes of AD that could point to more effective curative approaches for this condition.

Prof. Sultan Darvesh Darvesh
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Enzymatic Functions
  • Non-Enzymatic Functions
  • Neuroinflammation
  • Drug Development
  • Neuroimaging

Published Papers (3 papers)

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Research

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24 pages, 1926 KiB  
Article
Exploring Biological Activity of 4-Oxo-4H-furo[2,3-h]chromene Derivatives as Potential Multi-Target-Directed Ligands Inhibiting Cholinesterases, β-Secretase, Cyclooxygenase-2, and Lipoxygenase-5/15
by Malose J. Mphahlele, Emmanuel N. Agbo, Samantha Gildenhuys and Itumeleng B. Setshedi
Biomolecules 2019, 9(11), 736; https://doi.org/10.3390/biom9110736 - 13 Nov 2019
Cited by 13 | Viewed by 2947
Abstract
A series of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their hydrazone derivatives were evaluated as potential multi-target-directed ligands in vitro against cholinesterases, β-secretase, cyclooxygenase-2, and lipoxygenase-15 (LOX-15), as well as for free radical-scavenging activities. The most active compounds against LOX-15 were also evaluated [...] Read more.
A series of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their hydrazone derivatives were evaluated as potential multi-target-directed ligands in vitro against cholinesterases, β-secretase, cyclooxygenase-2, and lipoxygenase-15 (LOX-15), as well as for free radical-scavenging activities. The most active compounds against LOX-15 were also evaluated for activity against the human lipoxygenase-5 (LOX-5). Kinetic studies against AChE, BChE, and β-secretase (BACE-1) were performed on 2-(3-fluorophenyl)- (3b) and 2-(4-chlorophenyl)-6-[(4-trifluoromethylphenyl)hydrazonomethyl]furo[3,2-h]chromen-5-one (3e) complemented with molecular docking (in silico) to determine plausible protein-ligand interactions on a molecular level. The docking studies revealed hydrogen and/or halogen bonding interactions between the strong electron-withdrawing fluorine atoms of the trifluoromethyl group with several residues of the enzyme targets, which are probably responsible for the observed increased biological activity of these hydrazone derivatives. The two compounds were found to moderately inhibit COX-2 and lipoxygenases (LOX-5 and LOX-15). Compounds 3b and 3e were also evaluated for cytotoxicity against the breast cancer MCF-7 cell line and Hek293-T cells. Full article
(This article belongs to the Special Issue Cholinesterases in Alzheimer's Disease)
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7 pages, 1269 KiB  
Communication
Butyrylcholinesterase Protein Ends in the Pathogenesis of Alzheimer’s Disease—Could BCHE Genotyping Be Helpful in Alzheimer’s Therapy?
by Jacek Jasiecki and Bartosz Wasąg
Biomolecules 2019, 9(10), 592; https://doi.org/10.3390/biom9100592 - 9 Oct 2019
Cited by 36 | Viewed by 7734
Abstract
Late-onset Alzheimer’s disease (AD) is clinically characterized by a progressive decline of memory and other cognitive functions leading to the loss of the ability to perform everyday activities. Only a few drugs have been approved to treat AD dementia over the past century [...] Read more.
Late-onset Alzheimer’s disease (AD) is clinically characterized by a progressive decline of memory and other cognitive functions leading to the loss of the ability to perform everyday activities. Only a few drugs have been approved to treat AD dementia over the past century since the first AD patient was diagnosed. Drugs increasing the availability of neurotransmitters at synapses in the brain are used clinically in the treatment of AD dementia, and cholinesterase inhibitors (ChEIs) are the mainstay of the therapy. A detrimental effect on cognitive function has been reported in patients with pharmacological inhibition of acetylcholinesterase (AChE) by ChEIs and reduced butyrylcholinesterase (BChE) activity due to the single nucleotide polymorphisms. The BChE K-variant (rs1803274), the most common genetic variant of the BCHE gene, was thought to reduce enzyme activity reflecting the lower clinical response to rivastigmine in AD patients. During ChEIs therapy, patients carrying reduced-activity BChE do not present such improved attention like patients with the wild-type enzyme. On the other hand, alterations in the BCHE gene causing enzyme activity reduction may delay AD onset in patients at risk by preserving the level of cortical acetylcholine (ACh). Based on our previous results, we conclude that SNPs localized outside of the coding sequence, in 5’UTR (rs1126680) and/or intron 2 (rs55781031) of the BCHE gene, but not solely K-variant alteration (p.A539T) itself, are responsible for reduced enzyme activity. Therefore, we suspect that not BChE-K itself, but these coexisting SNPs (rs1126680 and rs55781031), could be associated with deleterious changes in cognitive decline in patients treated with ChEIs. Based on the results, we suggest that SNPs (rs1126680) and/or (rs55781031) genotyping should be performed to identify subjects at risk for lowered efficacy ChEIs therapy, and such patients should be treated with a lower rivastigmine dosage. Finally, our sequence analysis of the N-terminal end of N-BChE revealed evolutionarily conserved amino acid residues that can be involved in disulfide bond formation and anchoring of N-BChE in the cell membrane. Full article
(This article belongs to the Special Issue Cholinesterases in Alzheimer's Disease)
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Review

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21 pages, 2429 KiB  
Review
Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement
by Gabriela Dumitrita Stanciu, Andrei Luca, Razvan Nicolae Rusu, Veronica Bild, Sorin Ioan Beschea Chiriac, Carmen Solcan, Walther Bild and Daniela Carmen Ababei
Biomolecules 2020, 10(1), 40; https://doi.org/10.3390/biom10010040 - 26 Dec 2019
Cited by 150 | Viewed by 17852
Abstract
Alzheimer’s disease, a major and increasing global health challenge, is an irreversible, progressive form of dementia, associated with an ongoing decline of brain functioning. The etiology of this disease is not completely understood, and no safe and effective anti-Alzheimer’s disease drug to prevent, [...] Read more.
Alzheimer’s disease, a major and increasing global health challenge, is an irreversible, progressive form of dementia, associated with an ongoing decline of brain functioning. The etiology of this disease is not completely understood, and no safe and effective anti-Alzheimer’s disease drug to prevent, stop, or reverse its evolution is currently available. Current pharmacotherapy concentrated on drugs that aimed to improve the cerebral acetylcholine levels by facilitating cholinergic neurotransmission through inhibiting cholinesterase. These compounds, recognized as cholinesterase inhibitors, offer a viable target across key sign domains of Alzheimer’s disease, but have a modest influence on improving the progression of this condition. In this paper, we sought to highlight the current understanding of the cholinergic system involvement in Alzheimer’s disease progression in relation to the recent status of the available cholinesterase inhibitors as effective therapeutics. Full article
(This article belongs to the Special Issue Cholinesterases in Alzheimer's Disease)
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