Acetylcholinesterase promotes the aggregation of amyloid-β-peptide fragments by forming a complex with the growing fibrils 1 1Edited by A. R. Fersht

Álvarez, Alejandra; Opazo, Carlos; Alarcón, Rodrigo; Garrido, Jorge; Inestrosa, Nibaldo C.

doi:10.1006/jmbi.1997.1245

Cited by 289 publications

(194 citation statements)

References 59 publications

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“…98 Therefore, AChE directly promotes the formation of amyloid fibrils and stable Aβ-AChE complexes. 99 These complexes can change the pharmacologic and biochemical properties of AChE and increase the neurotoxicity of the Aβ fibrils. 100,101 Similarly, the addition of BuChE to Aβ in tissue culture results in a dramatic increase in neurotoxicity, although the mechanism underlying this effect is unknown.…”

Section: Potential Effects On Disease Progressionmentioning

confidence: 99%

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Grossberg

2003

Current Therapeutic Research

286

156

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Background: Cholinesterase (ChE) inhibitors currently used in the treatment of Alzheimer's disease (AD) are the acetylcholinesterase (AChE)-selective inhibitors, donepezil and galantamine, and the dual AChE and butyrylcholinesterase (BuChE) inhibitor, rivastigmine. In addition to differences in selectivity for AChE and BuChE, ChE inhibitors also differ in pharmacokinetic and pharmacodynamic properties, and these differences could significantly impact on safety, tolerability, and efficacy.Objective: The aim of this article was to provide an overview of the ChE inhibitors widely used in AD, focusing on key pharmacologic differences among agents and how these may translate into important differences in safety, tolerability, and efficacy in clinical practice.Methods: Using published literature collected over time by the author, a review was conducted, focusing on the pharmacology and clinical data of donepezil, galantamine, and rivastigmine.

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Section: Potential Effects On Disease Progressionmentioning

confidence: 99%

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Grossberg

2003

Current Therapeutic Research

286

156

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“…Colocalization of AChE and amyloid ␤-peptide deposits in the brain of Alzheimer's disease patients indicates a presence, if not an active role, in amyloid plaque formation (8 -11). AChE was demonstrated to accelerate the assembly of amyloid ␤-peptides into Alzheimer's fibrils, with a possible involvement of the peripheral anionic site (12,(61)(62)(63).…”

Section: Significance Of the Structurementioning

confidence: 99%

Crystal Structure of Mouse Acetylcholinesterase

Bourne¹,

Taylor²,

Bougis³

et al. 1999

Journal of Biological Chemistry

130

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The crystal structure of mouse acetylcholinesterase at 2.9-Å resolution reveals a tetrameric assembly of subunits with an antiparallel alignment of two canonical homodimers assembled through four-helix bundles. In the tetramer, a short ⍀ loop, composed of a cluster of hydrophobic residues conserved in mammalian acetylcholinesterases along with flanking ␣-helices, associates with the peripheral anionic site of the facing subunit and sterically occludes the entrance of the gorge leading to the active center. The inverse loop-peripheral site interaction occurs within the second pair of subunits, but the peripheral sites on the two loop-donor subunits remain freely accessible to the solvent. The position and complementarity of the peripheral site-occluding loop mimic the characteristics of the central loop of the peptidic inhibitor fasciculin bound to mouse acetylcholinesterase. Tetrameric forms of cholinesterases are widely distributed in nature and predominate in mammalian brain. This structure reveals a likely mode of subunit arrangement and suggests that the peripheral site, located near the rim of the gorge, is a site for association of neighboring subunits or heterologous proteins with interactive surface loops.

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“…The main features of AD development include, among others, the loss of cholinergic neurons (1), elevation of butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities (2) and accumulation of intra-and extracellular deposits of b-amyloid protein in the brain tissue (3). It has previously been shown that, apart from hydrolysis of acetylcholine, leading to deficits in the cholinergic pathways, AChE promotes the aggregation of b-amyloid protein followed by the formation of a complex with growing b-amyloid fibrils (4).…”

Section: Introductionmentioning

confidence: 99%

Phenolic acids from malt are efficient acetylcholinesterase and butyrylcholinesterase inhibitors

Szwajgier

Borowiec

2012

J. Inst. Brew.

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Anticholinesterase activities of mashes produced using wheat ('Wheat Pale') or barley malts ('Pilsner', 'Pale Ale', 'Munich Light', 'Carahell' or 'Carared') were studied by spectrophotometric method. The highest inhibition of acetylcholinesterase and butyrylcholinesterase was observed at 52 C and/or 64 C, followed by a decrease or stabilization of the activity at 72 C. Changes in the total phenolics content in the test mashes were correlated with changes in the acetylcholinesterase and/or butyrylcholinesterase activities. Phenolic acids were singled out from phenolic compounds for more detailed studies owing to their simplicity and structural similarity to well-known cholinesterase inhibitors. The main phenolic acids in the test malts were ferulic, gallic, p-coumaric and vanillic acids followed by chlorogenic, caffeic, syringic, p-OH-benzoic, sinapic and protocatechuic acids. The anticholinesterase activities of the phenolic acids were studied using model standard solutions at concentrations similar to the maximal content of these compounds in the test mashes. Among the phenolic acids, p-coumaric acid had the largest share in the anticholinesterase activity, even though it was present in the test mashes at a significantly lower concentration (~0.38 mM L À1 ) than ferulic acid (~1.00 mM L À1 ). Sinapic acid and p-OH-benzoic acid (0.03 and 0.01 mM L À1 , respectively) were equally efficient inhibitors as ferulic acid at~1.00 mM L À1 . This preliminary study should be extended to other phenolic compounds from malt (wort) in the near future.

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Acetylcholinesterase promotes the aggregation of amyloid-β-peptide fragments by forming a complex with the growing fibrils 1 1Edited by A. R. Fersht

Cited by 289 publications

References 59 publications

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Crystal Structure of Mouse Acetylcholinesterase

Phenolic acids from malt are efficient acetylcholinesterase and butyrylcholinesterase inhibitors

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