Molecular Mechanism of the Inhibition of EGCG on the Alzheimer Aβ<sub>1–42</sub>Dimer

Zhang, Tong; Zhang, Jian; Derreumaux, Philippe; Mu, Yuguang

doi:10.1021/jp312573y

Cited by 186 publications

(287 citation statements)

References 66 publications

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“…Although there are multiple binding modes of action, the analysis of intermolecular contact maps shows the NQTrp molecule binds strongly to the CHC and FL regions, reducing therefore the strength of the interpeptide interactions among residues 16−35, interactions that are seen in many simulations of Aβ1−40 and Aβ1−42 dimers in the absence of inhibitors. 17,[25][26][27][28][29][30][31][32]45 Our result is also in agreement with a recent hydrogen−deuterium exchange coupled with mass spectrometry study showing that the region of residues 20−35 is the first to aggregate, followed by the region of residues 36−42 and then the region of residues 1−19 during Aβ1−42 oligomerization. 46 At the residual and atomic level, we have determined that the NQTrp molecules bind mostly to the side chains of residues Arg5, Asp7, Tyr10, His13, Lys16, Phe19/Phe20, Lys28, and Leu34/Met35.…”

Section: ■ Discussionsupporting

confidence: 91%

“…At equilibrium, the population of free Aβ42 monomers is 0% in the presence of NQTrp, while in the presence of 10 EGCG molecules, there is a population of 5.2% of free Aβ42 monomers that would be able to associate with larger toxic and nontoxic aggregates. 30 Carnosine was found to be in contact with Aβ1−42 monomer for only 20% of the simulation time at 300 K and at a concentration of 5 mM versus a concentration of 11 mM in our study.…”

Section: ■ Conclusioncontrasting

confidence: 54%

“…30 Via comparison with our pattern of interactions with NQTrp, the hot residues Arg5, Asp7, Tyr10, Phe19/Phe20, and Met35 are recovered, but overall, the sites with the highest interaction probability are clearly different.…”

Section: ■ Discussionmentioning

confidence: 80%

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Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

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Aggregation of the amyloid β protein (Aβ) peptide with 40 or 42 residues is one key feature in Alzheimer's disease (AD). The 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp) molecule was reported to alter Aβ self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with Aβ peptides spanning the regions of residues 12−28 and 17−42, none of these studies were conducted on the fulllength Aβ1−42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1−42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and Aβ1−42, which change the Aβ interface by reducing most of the intermolecular contacts, are found to be very dynamic and multiple, leading to many transient binding sites. The most favorable binding residues are Arg5, Asp7, Tyr10, His13, Lys16, Lys18, Phe19/Phe20, and Leu34/Met35, providing therefore a completely different picture from in vitro and in silico experiments with NQTrp with shorter Aβ fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of Aβ1−42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting Aβ1−42 dimer against AD.

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Section: ■ Discussionsupporting

confidence: 91%

Section: ■ Conclusioncontrasting

confidence: 54%

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Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

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“…The dimer simulations starting from the amyloid fibrillar states and totaling 4.4 μs also reveal noticeable changes in terms of secondary structure, salt bridge, and topology. Overall, this study provides physical insights into the enhanced rate of fibril formation upon D7N mutation and an atomic picture of the D7N-mediated conformational change on Aβ 40 and Aβ 42 peptides. KEYWORDS: Amyloid simulation, Alzheimer's disease, amyloid-β proteins, molecular dynamics, D7N mutation, monomer, dimer A lzheimer's disease (AD) is the most common form of dementia among the senior population.…”

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confidence: 89%

Effect of the Tottori Familial Disease Mutation (D7N) on the Monomers and Dimers of Aβ₄₀ and Aβ₄₂

Man

Nguyen

Ngo

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:Recent experiments have shown that the mutation Tottori (D7N) alters the toxicity, assembly and rate of fibril formation of the wild type (WT) amyloid beta (Aβ) Aβ 40 and Aβ 42 peptides. We used all-atom molecular dynamics simulations in explicit solvent of the monomer and dimer of both alloforms with their WT and D7N sequences. The monomer simulations starting from a random coil and totaling 3 μs show that the D7N mutation changes the fold and the network of salt bridges in both alloforms. The dimer simulations starting from the amyloid fibrillar states and totaling 4.4 μs also reveal noticeable changes in terms of secondary structure, salt bridge, and topology. Overall, this study provides physical insights into the enhanced rate of fibril formation upon D7N mutation and an atomic picture of the D7N-mediated conformational change on Aβ 40 and Aβ 42 peptides. KEYWORDS: Amyloid simulation, Alzheimer's disease, amyloid-β proteins, molecular dynamics, D7N mutation, monomer, dimer A lzheimer's disease (AD) is the most common form of dementia among the senior population.1 The patient with AD will lose memory, 2 decay language, 3 and experience problems with visual-spatial search, 4 among other side-effects. AD is pathologically characterized by brain lesions that are senile plaques made of the beta amyloid (Aβ) peptides 5 and neurofibrillary tangles inside neurons made of the tau protein. 6 However, there is strong evidence that the Aβ peptides play a central role in AD. 7,8 The Aβ peptides are proteolytic byproducts of the amyloid precursor protein and are most commonly composed of 40 (Aβ 40 ) and 42 (Aβ 42 ) amino acids. The Aβ monomers are mostly random coil in physiological buffers, but aggregate to form amyloid fibrils with a cross-β-sheet pattern. 9−11Presently, there are no efficient drugs against AD. One current strategy, based on the fact that the aesthetic of the cerebral defects in AD correlates with high levels of oligomers in the brain, 12,13 is to design molecules preventing amyloid fibril formation and targeting the early formed toxic aggregates. 5,7,14−18 The another strategy is to design molecules enhancing fibril formation and reducing therefore the lifetimes of Aβ oligomers. 19 Unfortunately, because these assemblies are in dynamic equilibrium, experiments have failed thus far to provide atomic structures that would help design more efficient molecules in both scenarios.Numerous pathogenic familial mutations are known to modulate fibril formation rates and enhance toxicity. There has been many experimental studies on the Flemish (A21G), Dutch (E22Q), Italian (E22K), Arctic (E22G), Iowa (D23N), and Osaka (ΔE22, deletion) variants. 20−25 The English (H6R), 26Taiwanese (D7H), 27 and Tottori (D7N) 28 mutations that cause early onset familial AD have also been reported. The English and Tottori mutations do not affect Aβ production, but they accelerate fibril assembly in the absence of increased protofibril formation.29 A more recent experimental study showed that the Tottori mutation alters ...

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“…It seems that ECGC might also have protective effects on AD: in 2012 He et al [154] evaluated the beneficial effects of ECGC by immunohistochemical analysis of APP in the hippocampus of an AD mouse model. Further, Zhang et al [155] reported that the polyphenol (-)-EGCG is able to inhibit Aβ oligomerization.Homotaurine also deserves a specific mention. Homotaurine is a molecule that has been extensively investigated as a neuroprotector in AD.…”

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confidence: 99%

Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

Pescosolido¹,

Pascarella²,

Buomprisco³

et al. 2014

AOVS

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two distinct pathologies, despite similar pathophysiology and demographic distribution. Both diseases are neurodegenerative, chronic and progressive in nature, with irreversible neuronal cell loss. Furthermore, both POAG and AD disease primarily affect the elderly, with a strongly age-dependent incidence. The progressive debilitating course of both diseases has tremendous implications on an aging population [1]. For years Glaucoma has been associated with high IOP [2], although scientists had accepted this etiology with caution, since it was known that POAG could develop in subjects with normal or even low IOP. In fact, one out of three POAG patients has normotensive or low tension glaucoma [3]. This observation has led the scientific community to look for other possible causes of this slowly debilitating pathogenesis.The hallmark of neurodegenerative diseases is the death of specific neuron populations, and of those other neurons that are inter-connected and depend for their survival on the inputs from the main population (trans-synaptic degeneration). In Parkinson's disease accumulation of alfa-synuclein [4] causes the degeneration of dopaminergic neurons of the substantia nigra, in the midbrain, thus leading to the classic symptoms of Parkinson's such as tremor, akinesia, bradykinesia, and stiffness [5]. In AD there is a loss of neurons in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus [6]. Both amyloid plaques and neurofibrillary tangles are AbstractA third of people affected by primary open angle glaucoma (POAG) have normal or even low intraocular pressure (IOP), such as in the case of normotensive glaucoma and low pressure glaucoma. Therefore, high IOP, while remaining the most important risk factor for POAG development, is not the only one. POAG has been recognized to belong to the class of neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's, and several recent studies have suggested possible links between Alzheimer's and glaucoma both from an epidemiological and a pathogenetic point of view. In fact, several pathogenetic factors are common between the two diseases: the diffuse axonal degeneration of ganglion cells, the presence of specific markers (such as amyloid-β) in the aqueous humor, the activation of caspases and the abnormal processing of amyloid precursor protein in retinal ganglion cells, the reduction of the intracranial pressure of the cerebrospinal fluid, the mutations of the gene that encodes for optineurine. Conflicting data have been reported concerning apolipoprotein E. Finally, numerous publications affirm the utility of molecules traditionally used in the treatment of neurodegenerative diseases (e.g. forskolin, L-carnosine, homotaurine, folic acid, acetylcholinesterase inhibitors, antioxidant vitamins, glatiramer acetate, etc.) also in the treatment of glaucoma.In the present research we ana...

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Molecular Mechanism of the Inhibition of EGCG on the Alzheimer Aβ_1–42Dimer

Cited by 186 publications

References 66 publications

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Effect of the Tottori Familial Disease Mutation (D7N) on the Monomers and Dimers of Aβ₄₀ and Aβ₄₂

Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

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Molecular Mechanism of the Inhibition of EGCG on the Alzheimer Aβ1–42Dimer

Cited by 186 publications

References 66 publications

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Effect of the Tottori Familial Disease Mutation (D7N) on the Monomers and Dimers of Aβ40 and Aβ42

Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

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Molecular Mechanism of the Inhibition of EGCG on the Alzheimer Aβ_1–42Dimer

Effect of the Tottori Familial Disease Mutation (D7N) on the Monomers and Dimers of Aβ₄₀ and Aβ₄₂