The cholinergic hypothesis of Alzheimer's disease: a review of progress

Babić, Tomislav; Francis, Paul T.; PALMER, A. M; SNAPE, M.; WILCOCK, G. K

doi:10.1136/jnnp.67.4.558

Cited by 82 publications

(50 citation statements)

References 2 publications

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“…23 These 8 This oxidative stress affects the cholinergic transmission system, which explains the underlying cholinergic deficit in AD patients. 24 Several efforts have been made to elucidate the mechanism of ROS production due to the interaction of Ab fibrils and Cu 21 ; 8 however, the effect of Cu 21 and other metals on the oligomerization process is not well defined, and different authors have reported contradictory results. Some reports have demonstrated that Cu 21 favors the aggregation of Ab .…”

Section: Discussionmentioning

confidence: 99%

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

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The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1–42) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α‐helix to a β‐sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+ and various drugs used for AD treatment, such as galanthamine (Reminyl®), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu2+ and galanthamine prevent the formation of Aβ1–42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1–42 acquires a characteristic U‐shape before the α‐helix to β‐sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ1−42 in the presence of Cu2+ or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1−42 from adopting the U‐characteristic conformation that allows the amino acids to transition to a β‐sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu2+ and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils.

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Section: Discussionmentioning

confidence: 99%

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

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“…9 Degeneration of nuclei in the basal forebrain results in a loss of excitatory cholinergic transmission to the cerebral cortex and this is thought to contribute significantly to the cognitive deficits present in Alzheimer's disease. 10 Depletion of the neurotransmitter acetylcholine in AD due to reduced number of acetylcholine receptor and increased activity of acetylcholine-esterase are considered as prominent features of AD. In Alzheimer's disease, cortical cholinergic innervations are reduced leading to shifting of tau protein to its hyperphosphorylated form.…”

Section: Introductionmentioning

confidence: 99%

In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer's disease

Islam¹,

Zaman²,

Jahan³

et al. 2013

Journal of Young Pharmacists

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a b s t r a c tAcetylcholine-esterase (AchE) inhibitors are one of the most potent drug molecules against Alzheimer's disease (AD). But, patients treated with current AchE inhibitors often experience severe side effects. Quercetin is a plant flavonoid compound which can act as AchE inhibitor and it may be a better alternative to current AchE inhibitors in terms of effectiveness with no or fewer side effects. Aims: The aim of the study was to compare quercetin with conventional AchE inhibitors to search for a better drug candidate. Methods and materials: Physico-chemical properties of conventional drugs and quercetin were predicted using bioinformatics tools. Molecular docking of these compounds on the active site of AchE was performed using AutoDock and comparative analysis was performed. Later, modification on the basic structure of quercetin with different functional groups was done to perform QSAR analysis. Result and discussion: Quercetin showed a similar drug likeness score to the conventional drugs. The binding strength for quercetin in the active site of the enzyme was À8.8 kcal/mol, which was considerably higher than binding scores for some of the drugs such as donepezil (binding score À7.9 kcal/mol). Fifteen hydrogen bonds were predicted between quercetin and the enzyme whereas conventional drugs had fewer or even no hydrogen bonds. It implies that quercetin can act as a better inhibitor than conventional drugs. To find out even better inhibitor, similar structures of quercetin were searched through SIMCOMP database and a methylation in the 4-OH position of the molecule showed better binding affinity than parent quercetin. Quantitative structure activity relationship study indicated that O-4 methylation was specifically responsible for better affinity. Conclusion: This in silico study has conclusively predicted the superiority of the natural compound quercetin over the conventional drugs as AchE inhibitor and it sets the need for further in-vitro study of this compound in future.

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“…A central hallmark of this disease is a deterioration of learning and memory as well as other cognitive symptoms leading to a profound negative impact on the patient's daily life (Babic, 1999;Bianchetti et al, 2006;Brodaty et al, 2001). Alzheimer's disease accounts for at least 50e75% of dementia cases and represents the most common cause of dementia among the elderly (Aguero-Torres et al, 1998;Povova et al, 2012;Ropacki and Jeste, 2005;Suh et al, 2001).…”

Section: Alzheimer's Diseasementioning

confidence: 96%

Neuronal histamine and cognitive symptoms in Alzheimer's disease

et al. 2016

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The cholinergic hypothesis of Alzheimer's disease: a review of progress

Cited by 82 publications

References 2 publications

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer's disease

Neuronal histamine and cognitive symptoms in Alzheimer's disease

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The cholinergic hypothesis of Alzheimer's disease: a review of progress

Cited by 82 publications

References 2 publications

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer's disease

Neuronal histamine and cognitive symptoms in Alzheimer's disease

Contact Info

Product

Resources

About

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process