EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

Bieschke, Jan; Russ, Jenny; Friedrich, Ralf P.; Ehrnhoefer, Dagmar E.; Wobst, Heike J.; Neugebauer, Katja; Wanker, Erich E.

doi:10.1073/pnas.0910723107

Cited by 899 publications

(998 citation statements)

References 29 publications

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“…73 Moreover, EGCG has the ability to convert large amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic and therefore suggesting that EGCG is a potent remodeling agent of mature amyloid fibrils. 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).…”

Section: ■ Flavonoidsmentioning

confidence: 99%

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: 99%

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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“…EGCG degrades fibrils of transthyretin [96]; fibrils of merozoite surface protein 2 are also transformed into an amorphous structure by EGCG [103]. We were able to elucidate the mechanism by which EGCG acts on αS and Aβ fibrils [104].…”

Section: Disassembly and Remodeling Of Amyloid Depositsmentioning

confidence: 96%

“…3a) that do not bind to thioflavin T, do not catalyze seeding-induced aggregation, and that are not toxic in neuronal (SHSY5Y, PC12) cell models [104]. They possess the same properties as the off-pathway aggregates that are formed in the presence of monomeric αS and Aβ in the presence of EGCG.…”

Section: Disassembly and Remodeling Of Amyloid Depositsmentioning

confidence: 99%

“…They possess the same properties as the off-pathway aggregates that are formed in the presence of monomeric αS and Aβ in the presence of EGCG. In the neuronal cell model Aβ aggregates are degraded after treatment with EGCG [104].…”

Section: Disassembly and Remodeling Of Amyloid Depositsmentioning

confidence: 99%

“…In order to differentiate between these two possibilities, fluorescent markers were incorporated into Aβ fibrils [104]. If red-tagged fibrils are mixed with green-tagged fibrils, a mechanism in which dissociation of the fibrils is followed by re-aggregation should lead to amorphous aggregates containing similar amounts of both red-and green-tagged monomers.…”

Section: Mechanisms Of Amyloid Fibril Remodelingmentioning

confidence: 99%

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Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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Nanotechnology for Cerebral Delivery of Nutraceuticals for the Treatment of Neurodegenerative Diseases

Sahni

Doggui²,

Dao

et al. 2011

Functional Foods, Nutraceuticals, and Degenerative Disease Prevention

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EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

Cited by 899 publications

References 29 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

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Nanotechnology for Cerebral Delivery of Nutraceuticals for the Treatment of Neurodegenerative Diseases

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