The Anti-Amyloidogenic Effect Is Exerted against Alzheimer's β-Amyloid Fibrils in Vitro by Preferential and Reversible Binding of Flavonoids to the Amyloid Fibril Structure

Hirohata, Mie; Hara, Kazuhiro; Tsutsumi-Yasuhara, Shinobu; Ohhashi, Yumiko; Ookoshi, Tadakazu; Ono, Kenjiro; Yamada, Masahito; Naiki, Hironobu

doi:10.1021/bi061540x

Cited by 154 publications

(124 citation statements)

References 43 publications

(61 reference statements)

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“…74 Besides EGCG, other flavonoids have also shown antiamyloidogenic properties especially myricetin, that exerts an antiamyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of Aβ, rather than to Aβ monomers. 75,76 Overall, these studies suggest that certain flavonoids are able to disrupt fibrillization by leading to the production of off-target Aβ oligomers, function as BACE-1 inhibitors or act by enhancing ADAM10 activity, consequently reducing Aβ production (Figure 3). However, more studies are needed to discover which flavonoid structures have the greatest beneficial potential and their underlying mechanisms of action.…”

Section: ■ Flavonoidsmentioning

confidence: 98%

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Baptista

Henriques

Silva

et al. 2014

ACS Chem. Neurosci.

162

111

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Alzheimer's disease is characterized by pathological aggregation of protein tau and amyloid-β peptides, both of which are considered to be toxic to neurons. Naturally occurring dietary flavonoids have received considerable attention as alternative candidates for Alzheimer's therapy taking into account their antiamyloidogenic, antioxidative, and anti-inflammatory properties. Experimental evidence supports the hypothesis that certain flavonoids may protect against Alzheimer's disease in part by interfering with the generation and assembly of amyloid-β peptides into neurotoxic oligomeric aggregates and also by reducing tau aggregation. Several mechanisms have been proposed for the ability of flavonoids to prevent the onset or to slow the progression of the disease. Some mechanisms include their interaction with important signaling pathways in the brain like the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate prosurvival transcription factors and gene expression. Other processes include the disruption of amyloid-β aggregation and alterations in amyloid precursor protein processing through the inhibition of β-secretase and/or activation of α-secretase, and inhibiting cyclin-dependent kinase-5 and glycogen synthase kinase-3β activation, preventing abnormal tau phosphorylation. The interaction of flavonoids with different signaling pathways put forward their therapeutic potential to prevent the onset and progression of Alzheimer's disease and to promote cognitive performance. Nevertheless, further studies are needed to give additional insight into the specific mechanisms by which flavonoids exert their potential neuroprotective actions in the brain of Alzheimer's disease patients. KEYWORDS: Flavonoids, Alzheimer's disease, amyloid precursor protein, amyloid beta, BACE-1, tau, signaling A lzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia worldwide. The major histopathological hallmarks of AD include proteinous aggregates in the form of neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau 1,2 and extracellular senile plaques, which are deposits of heterogeneously sized small peptides of amyloid-β (Aβ) that are formed via sequential proteolytic cleavages of the amyloid precursor protein (APP) 3 (Figure 1). Dominant mutations in APP, presenilin-1 (PS1) or PS2 are responsible for the early onset or familial form of AD. These mutations have been shown to profoundly alter APP metabolism, favoring the production of aggregation-prone Aβ species, these findings formed the basis for the "amyloid cascade hypothesis" of AD pathogenesis. This broadly accepted hypothesis states that the generation of neurotoxic Aβ peptides by β-secretase and γ-secretase are at the basis of AD pathophysiology. Other hallmarks of this disease, like neurotransmitter changes 4,5 and neuronal and synapse loss in the neocortex and the hippocampus 6,7 develop as a consequence of this event.■ AMYLOID PRECURSOR PROTEIN APP belongs to a protein f...

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Section: ■ Flavonoidsmentioning

confidence: 98%

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Baptista

Henriques

Silva

et al. 2014

ACS Chem. Neurosci.

162

111

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“…56 For the effect on AD pathogenesis, there have been reports that RA reduces A␤-induced neurotoxicity 57,58 and protects against reactive oxygen species induced by A␤ in cell culture experiments. 58 In intracerebroventricular A␤ [25][26][27][28][29][30][31][32][33][34][35] injection mice model studies, i.p. injection of RA prevents memory impairment and A␤-induced neurotoxicity by scavenging ONOO Ϫ .…”

Section: Phenolic Compounds Prevent Ad Pathology 2561mentioning

confidence: 99%

“…26 To date, it has been reported that various compounds inhibit the formation and extension of A␤ fibrils, as well as destabilizing A␤ fibrils in vitro. 19,20,[27][28][29][30][31][32][33][34][35][36] Among the reported compounds, several phenolic compounds, such as wine-related polyphenols (myricetin (Myr), morin, and tannic acid, and so on), curcumin (Cur), ferulic acid (FA), nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA) had especially strong anti-A␤ aggregation effects in vitro. Furthermore, it was shown recently that a commercially available grape seed polyphenolic extract, MegaNatural-Az, inhibited fibril formation, protofibril formation, and oligomerization of A␤.…”

mentioning

confidence: 99%

Phenolic Compounds Prevent Alzheimer’s Pathology through Different Effects on the Amyloid-β Aggregation Pathway

Hamaguchi

Ono

Murase

et al. 2009

The American Journal of Pathology

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Inhibition of amyloid-␤ (A␤) aggregation is an attractive therapeutic strategy for Alzheimer's disease (AD). Certain phenolic compounds have been reported to have anti-A␤ aggregation effects in vitro.This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA-and RA-treated groups, A␤ deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group , the level of Trisbuffered saline (TBS)-soluble A␤ monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was decreased (P < 0.001). However, in the NDGA-treated group, the abundance of A11-positive oligomers was increased (P < 0.05) without any change in the levels of TBS-soluble or TBS-insoluble A␤. In the curcumin-and myricetin-treated groups, changes in the A␤ profile were similar to those in the RA-treated group, but A␤ plaque deposition was not significantly decreased. In the ferulic acid-treated group, there was no significant difference in the A␤ profile. These results showed that oral administration of phenolic compounds prevented the development of AD pathology by affecting different A␤ aggregation pathways in vivo. Clinical trials with these compounds are necessary to confirm the anti-AD effects and safety in humans. Alzheimer's disease (AD) is the most common form of dementia, resulting in deterioration of cognitive function and behavioral changes.1 One of the pathological hallmarks of AD is extracellular deposits of aggregated amyloid-␤ protein (A␤) in the brain parenchyma (senile plaques) and cerebral blood vessels (cerebral amyloid angiopathy (CAA)).1 Deposition of high levels of fibrillar A␤ in the AD brain is associated with loss of synapses, impairment of neuronal functions, and loss of neurons. 2-5A␤ was sequenced from meningeal vessels and senile plaques of AD patients and individuals with Down's syndrome.6 -8 The subsequent cloning of the gene encoding the ␤-amyloid precursor protein and its localization to chromosome 21, 9 -12 coupled with the earlier recognition that trisomy 21 (Down's syndrome) invariably leads to the neuropathology of AD, 13 set the stage for the proposal that A␤ accumulation is the primary event in AD pathogenesis. In addition, certain mutations associated with familial AD have been identified within or near the A␤ region of the coding sequence of gene of the amyloid precursor proteins, 14,15 presenilin-1 and presenilin-2, 16 which alter amyloid precursor protein metabolism through a direct effect on ␥-secretase. 17,18 These findings set the stage for the proposal that A␤ aggregation is the primary event in AD pathogenesis and leading to the proposal that anti-A␤ aggregation is a strategy for AD therapy.

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“…Wine-related polyphenols isolated by high performance liquid chromatography have been shown to inhibit the formation of A␤ fibrils as well as to dissociate preformed fibrils by preferentially and reversibly binding to these structures (23)(24)(25). For example, tannic acid, myricetin, morin, and quercetin inhibited fibril formation by Ͼ70% (23,24).…”

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confidence: 99%

Effects of Grape Seed-derived Polyphenols on Amyloid β-Protein Self-assembly and Cytotoxicity*

Ono

Condron

et al. 2008

Journal of Biological Chemistry

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Epidemiological evidence suggests that moderate consumption of red wine reduces the incidence of Alzheimer disease (AD). To study the protective effects of red wine, experiments recently were executed in the Tg2576 mouse model of AD. These studies showed that a commercially available grape seed polyphenolic extract, MegaNatural-AZ (MN), significantly attenuated AD-type cognitive deterioration and reduced cerebral amyloid deposition (Wang, J., Ho, L., Zhao, W., Ono, K., Rosensweig, C., Chen, L., Humala, N., Teplow, D. B., and Pasinetti, G. M. (2008) J. Neurosci. 28, 6388 -6392). To elucidate the mechanistic bases for these observations, here we used CD spectroscopy, photo-induced cross-linking of unmodified proteins, thioflavin T fluorescence, size exclusion chromatography, and electron microscopy to examine the effects of MN on the assembly of the two predominant disease-related amyloid ␤-protein alloforms, A␤40 and A␤42. We also examined the effects of MN on A␤-induced cytotoxicity by assaying 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide metabolism and lactate dehydrogenase activity in A␤-treated, differentiated pheochromocytoma (PC12) cells. Initial studies revealed that MN blocked A␤ fibril formation. Subsequent evaluation of the assembly stage specificity of the effect showed that MN was able to inhibit protofibril formation, pre-protofibrillar oligomerization, and initial coil 3 ␣-helix/␤-sheet secondary structure transitions.

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The Anti-Amyloidogenic Effect Is Exerted against Alzheimer's β-Amyloid Fibrils in Vitro by Preferential and Reversible Binding of Flavonoids to the Amyloid Fibril Structure

Cited by 154 publications

References 43 publications

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Phenolic Compounds Prevent Alzheimer’s Pathology through Different Effects on the Amyloid-β Aggregation Pathway

Effects of Grape Seed-derived Polyphenols on Amyloid β-Protein Self-assembly and Cytotoxicity*

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