2014年06月11日

Zemi 11-6-2014 (Amira)

Food & Function


Dietary polyphenol-derived protection against neurotoxic b-amyloid protein:
from molecular to clinical

Scott D. Smid, Jesper L. Maag and Ian F. Musgrave

Introduction:
Alzheimer’s disease is a form of dementia with symptoms including cognitive impairment and memory loss4 caused mainly by the loss of cholinergic neurons in the limbic system, neurocortex and hippocampus. The pathological hallmarks of Alzheimer’s disease are the deposition of beta-amyloid protein (Aβ) and hyper-phosphorylation of tau, which elicit neuronal cell death and impair neuronal communication. High levels of Aβ are found in the brains of patients with Alzheimer’s disease. The presence of Aβ is associated with neuronal inflammation, excitotoxicity and oxidative stress. Aβ also forms reactive oxygen species which can further enhance the formation of Aβ peptides and cause neuronal damage via lipid peroxidation, DNA damage and protein oxidation. So most of the recent studies search for the efficacy of antioxidant therapies to either ameliorate or otherwise mitigate against neuronal damage. Aβ’s ability to act as a generator of oxidative stress by itself depends critically on metal ions. Aβ is able to bind Cu2+, Zn2+ and Fe3+ to a lesser extent, all of which can induce Aβ aggregation and result in the generation of hydrogen peroxide and oxidative stress. drugs targeting metal ions in animal models of AD successfully limit the disease process and there are encouraging results in early human trials. In respect of natural products, polyphenolics e.g epigallicatechin-3-gallate (EGCG), curcumin have a demonstrated capacity to chelate metal ions and part of their anti-Alzheimer’s activity may be attributed to this property

Aim of this review:

This review focuses mostly on some of candidate polyphenolic flavonoids as potential and specific anti-amyloid treatments, with inclusion of the stilbene resveratrol and curcumin. This focus is based on their antioxidant capacity, activation of cell-specific pathways for neuroprotection and via direct anti-amyloid interactions.
In vitro studies on amyloid neurotoxicity and antioxidants:
The author mentioned the limitation of the data available and also the use of polyphenolics as an effective treatment for neurotoxicity induced by Aβ peptides. The first is the research results are readings of in vitro studies on cell lines not from in vivo due to low bioavailability of polyphenolic compounds for central nervous system. the second is that antioxidant molecules can form pro-oxidant species by itself could be toxic to the cells. The last is that conventional antioxidants such as ascorbic acid and trolox failed to protect against neurotoxicity induced by H2O2..

Polyphenols altered protective pathways of neuronal cells:

Resveratrol among others that could protect neuronal PC12 cells against Aβ-mediated toxicity and lower ROS levels in neuronal cell culture via antioxidant capacity and an up-regulation of antioxidant defenses.
Curcumin consumption has been associated with a reductionin Aβ fibril formation due to antioxidant, improved genomic stability down-regulation of amyloid precursor protein processing and tau hyperphosphorylation
Natural product extracts: such as cinnamon extract and pomegranate juice, extracts of the fruit from Vitis vinifera, which includes extracts from both grape skin and seed. Grape skin and seed extracts are comprised of a mixture of red grape pigments containing pigmented tannins and anthocyanins. Such activity may be due to presence of proanthocyanidins.
Bioactive polyphenols as direct inhibitors of β-amyloid formation:
The author in this part concerns with polyphenols that actively disrupt mature or preformed fibrils.
Curcumin some studies have shown a direct inhibition of Aβ fibril aggregation and disruption of mature fibrils with this natural product derived from turmeric.
Resveratrol was to alter soluble oligomers and fibrils of Aβ into insoluble high molecular weight aggregates that are non-toxic.
Epigallocatechin-3-gallate: derived from green tea and it was found that is a novel β-sheet breaker.
Limitations in biochemical assays of bioactive polyphenolic effects on β-amyloid formation:
Varying findings with bioactive polyphenols in terms of Aβ fibril inhibition outcomes is the interference that polyphenols may introduce in some fluorescent and spectrophotometric assays used to measure Aβ fibril formation such as thioflavin (ThT). polyphenolics may interact with ThT directly or compete with its binding to fibrils generating false positives for fibril inhibition.

Structure–Function Activity Relationships:
 long, flexible molecule with terminals capable of significant hydrogen bonding, which can bridge between fibril formingmonomers leading to off-pathway aggregates, may be more effective than other kinds of molecules as small anti-amyloids.\

 Increasing the number of galloyl moiety increase the activity.



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