Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

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Alzheimer’s disease is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of Alzheimer’s disease is the accumulation of plaques in the brain of Alzheimer’s disease patients. The plaques predominantly consist of aggregates of amyloid-beta generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that amyloid-beta aggregates are ordered oligomers and the cause rather than a product of Alzheimer’s disease.

There are a number of studies that state that the accumulation of amyloid beta within the brain arises from an imbalance of the production and clearance of amyloid beta.  Most of the time in the case of Alzheimer’s disease, amyloid beta clearance is impaired.  1

The process of creating amyloid beta in the brain has multiple roles in the brain, including:  2

  • antioxidant activity
  • calcium homeostasis
  • metal ion sequestration
  • modulation of synaptic plasticity
  • neurogenesis
  • neurotrophic activity

This controlled homeostatic regulation allows for the normal functions of amyloid beta but also prevents accumulation of excess amyloid beta as a metabolic waste product. 

An imbalance in this homeostasis results in pathological and neurotoxic accumulations of cerebral amyloid beta.  3

Scientists have developed a number of therapeutic strategies as possible interventions against amyloid beta, two of which include:

  • Anti-aggregations agents
  • Clearance of amyloid beta

Anti-aggregations agents

Anti-aggregation prevent amyloid beta fragments from aggregating or clear aggregates once they are formed.  4

Clearance of amyloid beta

Impaired clearance of amyloid beta is now widely identified as a contributing factor towards Alzheimer’s disease progression.  5   In order to prevent pathological accumulations of amyloid beta in the brain, amyloid beta clearance from the cerebral milieu into periphery and out of the system is of prime importance. Improving amyloid beta clearance from the brain across the blood–brain barrier (BBB) and into blood plasma.

Clearance of amyloid beta is so important that recent evidence in humans suggests that impaired amyloid beta clearance is the main cause of pathological accumulations of cerebral amyloid beta in late onset Alzheimer’s disease and not the overproduction of amyloid beta.  6 

The purpose of this article is to examine and identify the natural compounds that act as either anti-aggregation agents or an agents for the clearance of amyloid beta, or both.  

Researchers have identified a number of natural compounds that have been effective as therapeutics for Alzheimer’s disease whether as an anti-aggregation agent and/or an agent for clearance of amyloid beta.  7 

These natural compounds include:

  • Baicalein
  • Curcumin
  • Ellagic acid
  • (−)-Epigallocatechin-3-gallate (EGCG)
  • Ferulic acid
  • Fisetin
  • Kaempferol
  • Luteolin
  • Malvidin
  • Melatonin
  • Myricetin
  • Nordihydroguaiaretic acid (NDGA)
  • Oleuropein Aglycone (OLE)
  • Proline Rich Polypeptide (Colostrinin™)
  • Quercetin
  • Resveratrol
  • Rosmarinic acid
  • Rutin
  • Vitamin A

Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

Natural CompoundAbstractReferences
BaicaleinOur data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-β peptide (Aβ) aggregation and toxicity. We found that baicalein can also inhibit Aβ fibrillation and oligomerisation, disaggregate pre-formed Aβ amyloid fibrils and prevent Aβ fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. 1
CurcuminWhen fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.2 2a
Ellagic acidHere, we tested the effects of ellagic acid (EA), a polyphenolic compound, on Abeta42 aggregation and neurotoxicity in vitro. EA promoted Abeta fibril formation and significant oligomer loss, contrary to previous results that polyphenols inhibited Abeta aggregation. 3
(−)-Epigallocatechin-3-gallate (EGCG)Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.4
The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.5
Ferulic acidFerulic acid dose-dependently inhibited fAbeta formation from amyloid beta-peptide, as well as their extension. Moreover, it destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: Cur > FA > rifampicin = tetracycline. FA could be a key molecule for the development of therapeutics for AD.6
Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.7
FisetinFisetin (3,3',4',7-tetrahydroxyflavone) has been found to be neuroprotective, induce neuronal differentiation, enhance memory, and inhibit the aggregation of the amyloid beta protein (Abeta) that may cause the progressive neuronal loss in Alzheimer's disease. 8
The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) is neurotrophic and prevents fibril formation of amyloid β protein (Aβ). It is a promising lead compound for the development of therapeutic drugs for Alzheimer's disease.  9
KaempferolKaempferol was shown to have protective effects against oxidative stress-induced cytotoxicity in PC12 cells. Administration of kaempferol also significantly reversed amyloid beta peptide (Abeta)-induced impaired performance in a Y-maze test.10
Luteolin These results indicated that luteolin from the Elsholtzia rugulosa exerted neroprotective effects through mechanisms that decrease AβPP expression, lower Aβ secretion, regulate the redox imbalance, preserve mitochondrial function, and depress the caspase family-related apoptosis.11
MalvidinWe have identified four novel polyphenols which could be efficient fibril inhibitors in Alzheimer's disease: malvidin and its glucoside and curculigosides B and D. We suggest that molecules with the particular C(6)-linkers-C(6) structure could be potent inhibitors. From the results reported for the flavan-3-ol family, their anti-amyloidogenic effects against whole peptides (1-40 and 1-42) could involve several binding sites.12
MelatoninWe report that melatonin, a hormone recently found to protect neurons against Abeta toxicity, interacts with Abeta1-40 and Abeta1-42 and inhibits the progressive formation of beta-sheets and amyloid fibrils. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.13
Inhibition of beta-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.14
MyricetinMyricetin was the most potent compound myricetin to the neurotoxic oligomers rather than monomers. These findings suggest that flavonoids, especially Myricetin, exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fAbeta, rather than to Abeta monomers.15
Nordihydroguaiaretic acid (NDGA)In cell culture experiments, fAbeta disrupted by NDGA were less toxic than intact fAbeta, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAbeta formation from Abeta, as well as breaking down pre-formed fAbetain vitro, are still unclear, NDGA could be a key molecule for the development of therapeutics for AD.16
Oleuropein Aglycone (OLE)Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to preformed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of soluble oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation molecule is discussed in the light of these data.17
Proline Rich Polypeptide (Colostrinin™)Colostrinin™ is a mixture of proline-rich polypeptides (PRP) from ovine (sheep) colostrums. Colostrinin inhibits amyloid beta aggregation and facilitates disassembly of existing aggregates by disrupting beta-sheets bonding.18
QuercetinQuercetin is an effective amyloid aggregation inhibitor and inhibits amyloid beta fibrillization, but not its toxic oligomerization19
ResveratrolHere we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. 20
In conjunction with the concept that Abeta oligomers are linked to Abeta toxicity, we speculate that aside from potential antioxidant activities, resveratrol may directly bind to Abeta42, interfere in Abeta42 aggregation, change the Abeta42 oligomer conformation and attenuate Abeta42 oligomeric cytotoxicity. 21
Rosmarinic acidRosmarinic acid had especially strong anti-amylid beta aggregation effects in vitro22
Rosmarinic acid reduced a number of events induced by Abeta. These include reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Moreover, rosmarinic acid inhibited phosphorylated p38 mitogen-activated protein kinase but not glycogen synthase kinase 3beta activation. These data show the neuroprotective effect of sage against Abeta-induced toxicity, which could validate the traditional use of this spice in the treatment of AD. Rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.23
RutinHere, we show that the common dietary flavonoid, rutin, can dose-dependently inhibit Aβ42 fibrillization and attenuate Aβ42-induced cytotoxicity in SH-SY5Y neuroblastoma cells. 24
Vitamin A (beta-carotene)In this study, we used fluorescence spectroscopy with thioflavin T (ThT) and electron microscopy to examine the effects of vitamin A (retinol, retinal, and retinoic acid), beta-carotene, and vitamins B2, B6, C, and E on the formation, extension, and destabilization of beta-amyloid fibrils (fAbeta) in vitro. Among them, vitamin A and beta-carotene dose-dependently inhibited formation of fAbeta from fresh Abeta, as well as their extension. Moreover, they dose-dependently destabilized preformed fAbetas.25
Withanolides (Withania somnifera)The researchers found that using Withania somnifera extracts, comprising 75% withanolides and 20% withanosides, reversed plaque pathology and reduced the amyloid beta burden in middle-aged and old APP/PS1 mice through up-regulation of liver LRPI, leading to increased clearance of amyloid beta.26

Cover Photo:  Rosemary plant and flower