A gorge-spanning, high-affinity cholinesterase inhibitor to explore β-amyloid plaques

Abstract

Cholinesterases are involved in the pathological formation of beta-amyloid plaques. To investigate this pathohistological hallmark of Alzheimer's disease we prepared a high-affinity, fluorescent cholinesterase inhibitor. Its fluorescence intensity was significantly enhanced upon binding to cholinesterases. Using this probe, brain samples from mice and humans affected by Alzheimer's disease were successfully analyzed for beta-amyloid plaques. Unexpectedly, it was discovered, by competition experiments, that the compound binds to amyloid structures, rather than to cholinesterases inside of the plaques.

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

“…Accumulation of amyloid β peptide (Aβ) deposits23, abnormal modification and accumulation of the protein tau4 accompanied with oxidative stress in the brain lead to synaptic dysfunction and neurodegeneration1. This most severely affects the cholinergic system5 and results in a decrease in the levels of the neurotransmitter acetylcholine (ACh)6, which in turn produces memory and cognitive deficits7, characteristic for patients with AD.…”

Chemical Biology: What is Its Role in Drug Discovery?

“…A key feature of the affinity label is that it requires unmasking by an intracellular esterase and the authors envisage applications in pulse-chase experiments and high-content screening amongst other protocols. Fluorescent cholinesterase inhibitors have been used to identify the formation of -amyloid plaques in brain samples from animals and humans affected with Alzheimer's disease (Elsinghorst et al, 2009). …”

Synthesis of a Fluorescent‐Labeled Bisbenzamidine Containing the Central (6,7‐Dimethoxy‐4‐coumaryl)Alanine Building Block

“…Miscellaneous types of fluorophores have been employed for manifold purposes. Besides BODIPY (boron‐dipyrromethene) and fluorescein derivatives, coumarins represent a widely used class of fluorescent dyes and are valued for their small molecular size and large Stokes shifts . Structure–fluorescence relationships of the coumarin chemotype revealed high fluorescence as a result of the introduction of an electron‐donating substituent at the 7‐position.…”