A key molecular mechanism implicated in diverse neurodegenerative diseases is protein misfolding, resulting in pathologic aggregation and accumulation of proteins in the brain [1
]. Compelling evidence strongly supports the hypothesis that accumulation of misfolded proteins leads to synaptic dysfunction, brain damage, and disease. However, the mechanism by which protein misfolding and aggregation trigger neurodegeneration and the identity of the neurotoxic structure are still unclear. Recent evidence indicates that certain grape-derived dietary compounds – in particular, certain polyphenolic compounds enriched in grape derived polyphenols – may interfere with abnormal protein folding, thereby reducing the accumulation of neurotoxic proteins.
Misfolding of the microtubule-associated protein tau, leading to the aggregation of tau into paired helical filaments that are ultimately deposited as NFTs, is a key neuropathologic feature among tauopathies [4
]. Based on our recent observation that a particular grape seed polyphenolic extract, namely Meganatural-Az, GSPE attenuates the generation and stability of misfolded proteins [5
], we hypothesized that this GSPE might also attenuate the tau protein misfolding that leads to the generation of tau aggregates critical for the initiation and progression of neurodegeneration and/or cognitive dysfunctions in tauopathies.
In this study, we used aggregations of synthetic Ac-306VQIVYK311 tau peptide as an in vitro model system to assess the potential role of Meganatural-Az® GSPE in preventing and/or treating tau-associated neurodegenerative disorders by interfering with the generation and/or stability of aggregated tau filament deposits in the brain.
We recently found that Meganatural-Az® GSPE inhibited the aggregation of AD-type Aβ
]. In the current study, we demonstrate that the Ac-306
tau peptide is also a substrate for the anti-oligomerization activity of GSPE. In particular, we found that GSPE is capable of inhibiting aggregations of the tau peptide into filaments, and dissociating pre-formed tau aggregates. Collectively, our observation suggests that interactions of Meganatural-Az® GSPE with tau may attenuate the accumulation of tau aggregate deposits, a key neuropathologic feature among multiple tau-associated neurodegenerative disorders.
We recently demonstrated that Meganatural-Az® GSPE is bioavailable at the organism level and exerts an anti-oligomerization activity in experimental model systems. In particular, we established that dietary supplementation with Meganatural-Az® GSPE reduces aggregations of Aβ
peptides into high molecular weight Aβ
oligomeric species in the brain of a transgenic mouse model of AD [6
Based on in vivo
bioavailability of Meganatural-Az® GSPE [6
] and in vitro
evidence from this study suggesting that GSPE mechanistically interferes with the generation of tau aggregates, we hypothesized that applications of this GSPE might be effective as a preventive measure to attenuate the onset of tauopathies by interfering with the generation of abnormal tau aggregates. In addition, based on our in vitro
evidence that Meganatural-Az® GSPE effectively dissociates pre-formed tau peptide aggregates, it might be possible to develop this GSPE as a therapy for treating tau-associated neurodegenerative disorders.
We found that low levels of Meganatural-Az® GSPE, at molar ratios less than the concentration of the Ac-306VQIVYK311 tau peptide, effectively reduced aggregations of the tau peptide while promoting the dissociation of preformed tau aggregates. This suggests that treatments with low dosages of Meganatural-Az® GSPE might be sufficient to provide beneficial disease-modifying bioactivities in tau-associated neurodegenerative disorders. Future in vivo studies using animal models of tauopathies will identify the most appropriate doses of Meganatural-Az® GSPE to test for preventive and/or therapeutic efficacy in humans.
Meganatural-Az® GSPE comprises of catechin and epicatechin in monomeric, dimeric oligomeric, and polymeric forms. In ongoing studies, we are identifying the specific polyphenolic component(s) responsible for anti-tau aggregation bioactivity of the GSPE. Hasegawa [11
] reported that epicatechin-3-gallate, which is structurally related to catechin, inhibits tau filament formation in vitro
. Thus, it is possible that catechin in the Meganatural-Az® GSPE might contribute to anti-tau aggregation bioactivity.
Evidence suggests that Meganatural-Az® GSPE is highly tolerable and safe in humans. A recent report found that a long-term oral application of up to 300 mg/day of this GSPE is not associated with observable aversive response [9
]. In animal modeling systems, long-term treatment with up to 200 mg/day has been shown to be tolerable and safe [6
]. Translating drug dosage from mice to an equivalent drug dosage in humans, using a United States Food and Drug Administration criterion that factors in body surface area in calculating equivalent drug dosages across species [human equivalent dose in mg/kg = animal dose in mg/kg × (animal weight in kg/human weight in kg)0.33
], we calculated that 200 mg/day of Meganatural-Az® GSPE in mice is equivalent to 1 g/day of the GSPE in humans. Thus, we anticipate that dosages of Meganatural-Az® GSPE, higher than 300 mg/day might be applicable in humans.
In conclusion, the demonstrated bioavailability as well as safety and tolerability of Meganatural-Az® GSPE, in conjunction with evidence from this study implicating the efficacy of this GSPE to modulate tau-mediated neuropathologic mechanisms, supports development of Meganatural-Az® GSPE for the prevention and/or treatment of tau-associated neurodegenerative disorders.