Stable Complexes Involving Acetylcholinesterase and Amyloid-β Peptide Change the Biochemical Properties of the Enzyme and Increase the Neurotoxicity of Alzheimer’s Fibrils

Álvarez, Alejandra; Alarcón, Rodrigo; Opazo, Carlos; Campos, Eliseo O.; Muñoz, Francisco J.; Calderón, Frances; Dajas, Federico; Gentry, Mary K.; Doctor, Bhupendra P.; Mello, Fernando G. de; Inestrosa, Nibaldo C.

doi:10.1523/jneurosci.18-09-03213.1998

Cited by 291 publications

(211 citation statements)

References 84 publications

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“…Neostigmine resulted in two IC 50 values, 50 Ϯ 25 M and 38 Ϯ 10 nM, based on two-site competition fitting. These numbers generally agreed well with previously reported values (eserine 72-109 nM [34], malathion 370 M [35], edrophonium 5.4 M [36], and neostigmine 11.3 nM [37]; however, direct comparison of these numbers might not be appropriate because the experimental conditions were not identical (e.g., use of surrogate substrates and different AchE in other assays).…”

Section: Ache Inhibitor Characterizationsupporting

confidence: 90%

Rapid and label-free screening of enzyme inhibitors using segmented flow electrospray ionization mass spectrometry

Pei

Kennedy

2010

J. Am. Soc. Mass Spectrom.

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Electrospray ionization mass spectrometry (ESI-MS) is an attractive analytical tool for high-throughput screening because of its rapid scan time and ability to detect compounds without need for labels. Impediments to the use of ESI-MS for screening have been the relatively large sample consumed and slow sample introduction rates associated with commonly used flow injection analysis. We have previously shown that by segmenting nanoliter plugs of sample with air, an array of discrete samples can be delivered to a platinum-coated emitter tip for ESI-MS analysis with throughput as high as 0.8 Hz and carry-over between samples less than 0.1%. This method was applied to screening for inhibitors of acetylcholinesterase as a demonstration of the potential of segmented flow ESI-MS for such applications. Each enzyme assay consumed 10 nL of sample. At 1 L/min infusion rate, 102 samples were analyzed, corresponding to a 0.65 Hz sample analysis rate. Linear quantification of choline was achieved from 200 M to 10 mM using this method and Z= values were over 0.8 for the assay. Detailed pharmacologic dose-response curves of selected inhibitors were also measured in high-throughput fashion to validate the method. (J Am Soc

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Section: Ache Inhibitor Characterizationsupporting

confidence: 90%

Rapid and label-free screening of enzyme inhibitors using segmented flow electrospray ionization mass spectrometry

Pei

Kennedy

2010

J. Am. Soc. Mass Spectrom.

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“…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. 102 These data suggest that rivastigmine, as a dual ChE inhibitor, may possess a greater disease-modifying potential than the AChE-specific inhibitors donepezil and galantamine, although further studies in this area are warranted.…”

Section: Potential Effects On Disease Progressionmentioning

confidence: 99%

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Grossberg

2003

Current Therapeutic Research

304

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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“…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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Stable Complexes Involving Acetylcholinesterase and Amyloid-β Peptide Change the Biochemical Properties of the Enzyme and Increase the Neurotoxicity of Alzheimer’s Fibrils

Cited by 291 publications

References 84 publications

Rapid and label-free screening of enzyme inhibitors using segmented flow electrospray ionization mass spectrometry

Rapid and label-free screening of enzyme inhibitors using segmented flow electrospray ionization mass spectrometry

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Crystal Structure of Mouse Acetylcholinesterase

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