Phenolic Compounds Prevent Amyloid β-Protein Oligomerization and Synaptic Dysfunction by Site-specific Binding

Ono, Kenjiro; Li, Lei; Takamura, Yusaku; Yoshiike, Yuji; Zhu, Li-Jun; Han, Fang; Mao, Xi‐an; Ikeda, Tokuhei; Takasaki, Jun-ichi; Nishijo, Hisao; Takashima, Akihiko; Teplow, David B.; Zagorski, Michael G.; Yamada, Masahito

doi:10.1074/jbc.m111.325456

Cited by 229 publications

(182 citation statements)

References 54 publications

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“…Only several years later did structural insights emerge with respect to the residues on Aβ to which these compounds bind. 18 Very recent work by Sinha and co-workers has described the identification of lysine and arginine residues as targets for anionic "molecular tweezers" that inhibit aggregation. 19,20 In contrast to this specific interaction, other compounds that show strong inhibitory interaction are poorly characterized by experimental methods.…”

mentioning

confidence: 99%

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

Lemkul

Bevan

2012

ACS Chem. Neurosci.

104

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The pathogenic aggregation of the amyloid β-peptide (Aβ) is considered a hallmark of the progression of Alzheimer's disease, the leading cause of senile dementia in the elderly and one of the principal causes of death in the United States. In the absence of effective therapeutics, the incidence and economic burden associated with the disease are expected to rise dramatically in the coming decades. Targeting Aβ aggregation is an attractive therapeutic approach, though structural insights into the nature of Aβ aggregates from traditional experiments are elusive, making drug design difficult. Theoretical methods have been used for several years to augment experimental work and drive progress forward in Alzheimer's drug design. In this Review, we will describe how two common techniques, molecular docking and molecular dynamics simulations, are being applied in developing small molecules as effective therapeutics against monomeric, oligomeric, and fibrillated forms of Aβ. Recent successes and important limitations will be discussed, and we conclude by providing a perspective on the future of this field by citing recent examples of sophisticated approaches used to better characterize interactions of small molecules with Aβ and other amyloidogenic proteins.

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mentioning

confidence: 99%

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

Lemkul

Bevan

2012

ACS Chem. Neurosci.

104

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show abstract

“…The therapeutic efficacy of RA has been tested in both in vitro and in vivo models of AD. Previous studies have been tested the effect of RA on Ab aggregation in both in vitro and transgenic mice model of AD [41,42]. It has been reported that RA prevents Ab oligomerization under in vitro conditions and that RA prevents Ab-induced alterations of neuronal plasticity in the CA1 region of mouse hippocampus slices [41].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have been tested the effect of RA on Ab aggregation in both in vitro and transgenic mice model of AD [41,42]. It has been reported that RA prevents Ab oligomerization under in vitro conditions and that RA prevents Ab-induced alterations of neuronal plasticity in the CA1 region of mouse hippocampus slices [41]. Oral administration of RA decreased the Ab burden in the AD model transgenic mice by inhibiting the Ab aggregation pathway from Ab monomers to A11-positive oligomers and from A11-positive oligomers to Ab deposition [42].…”

Section: Discussionmentioning

confidence: 99%

Effects of rosmarinic acid on cognitive and biochemical alterations in ovariectomized rats treated with D-galactose

Kantar

Ozturk

et al. 2016

Folia Histochem Cytobiol.

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Introduction. Animal models designed to mimic certain features of Alzheimer's disease (AD) can help us to increase our understanding of the underlying mechanisms of disease. Previous studies have revealed that long-term D-galactose injection combined with ovariectomy results in pathophysiologic alterations associated with AD. Thus, the aim of the present study was to investigate the effects of rosmarinic acid (RA) administration on pathological changes associated with ovariectomy and D-galactose injection, which serve as a two-insult model for AD. Material and methods. One hundred female Wistar rats were divided into five equal groups: control (C), Sham (Sh), rosmarinic acid treated (R), ovariectomized rats treated with D-galactose (OD), ovariectomized rats treated with D-galactose and rosmarinic acid (ODR) groups. D-galactose (80 mg/kg/day) was administered by i.p. injection and RA (50 mg/kg/day) was given via gavage for 60 days. Open field and Y-maze tests were used to assess locomotor activity and short-term spatial memory, respectively. Biochemical and histopathological analyses of the brain tissue were performed. Results. Open field testing showed that the locomotor activity and exploratory behavior of rats were prominently impaired in the OD group as compared to the other studied groups. Similarly, Y-maze test results revealed a decrease of short-term spatial memory in the OD rats. A concomitant treatment with RA significantly restored altered locomotor activity and cognitive functions in the ODR group. Lipid peroxidation levels, cyclooxygenase-2 expression and prostaglandin E2 levels in the brain tissue were higher in the OD group and RA treatment inhibited these changes. AD-like histopathological alterations and amyloid b peptide (Ab) depositions were observed in the OD group. Normal cell structure and lower Ab depositions were observed in the ODR group compared with the OD group. Conclusions. RA could have the potential to prevent some psychological and biochemical alterations of brain tissue found in a rat model of AD probably by attenuating lipid peroxidation and inflammatory response.

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“…Among natural compounds, most Aβ inhibitors present a polyphenolic core [42], including resveratrol [43], myricetin [44], curcumin [45], caffeine [46].…”

Section: Aβ Aggregation Inhibitormentioning

confidence: 99%

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

Pietrobono¹,

Giacomelli²,

Ml³

et al. 2017

Glob Drugs Therap

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Phenolic Compounds Prevent Amyloid β-Protein Oligomerization and Synaptic Dysfunction by Site-specific Binding

Cited by 229 publications

References 54 publications

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

Effects of rosmarinic acid on cognitive and biochemical alterations in ovariectomized rats treated with D-galactose

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

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