Grape Derived Polyphenols Attenuate Tau Neuropathology in a Mouse Model of Alzheimer's Disease

Abstract

Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to chromosome 17, and Pick's disease. Tau is abnormally hyperphosphorylated in AD and aberrant tau phosphorylation contributes to the neuropathology of AD and other tauopathies. Anti-aggregation and anti-phosphorylation are main approaches for tau-based therapy. In this study, we report that a select grape-seed polyphenol extract (GSPE) could potently interfere with the assembly of tau peptides into neurotoxic aggregates. Moreover, oral administration of GSPE significantly attenuated the development of AD type tau neuropathology in the brain of TMHT mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain.

Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes

“…Grape-derived bioactive GSE preparations comprising proanthocyanidins have been demonstrated to exert a wide scope of neuroprotective biological activities in animal models of tauopathy and neurodegeneration (33)(34)(35)(36)65). More complex proanthocyanidins, however, including dimers, trimers, and oligomers have a reduced bioavailability in the rat brain when compared with monomers (66).…”

“…We have shown that a natural product, grape seed polyphenolic extract (GSE), may attenuate misfolding of tau protein into fibrillar polymers by promoting deaggregation of preformed tau aggregates and authentic PHFs in cell-free conditions (31,32) and in animal studies using tau transgenic mouse models (33,34). Deaggregation may lead to enhanced proteolytic clearance (35).…”

Protective effects of berry polyphenols against age-related cognitive impairment

“…Resveratrol was particularly effective in reducing, in a dose-dependent manner, the production of intracellular A␤ peptides via a proteasome-dependent mechanism [184]. In animals, oral administration of a grape-seed polyphenol extract containing resveratrol significantly attenuates the development of tau neuropathology in a mouse model of AD [185]. Treatment with a standardized grape polyphenol preparation containing resveratrol leads to the improvement of cognitive function and greatly reduces total amyloid content in the brain of J20 AD mice, an animal model of A␤ pathology [186].…”

Antioxidant Plant Polyphenols and Cognitive Disorders

“…Hyperphosphorylation of tau protein that causes its function disturbance and aggregation with subsequent formation of neuropil threads and neurofi brillary tangles in the brain is observed in numerous neurodegenerative disorders including AD. The same grape seed polyphenolic extract given in the dose of 200 mg/kg/day for 2 months inhibited accumulation of sarkosylinsoluble tau in the brain of TMHT mice, a model of age-dependent development of tau pathology (Wang et al 2010 ). Analysis of pulverized brain tissue lysates with ELISA-based multiplex cell signaling assays showed important suppression of ERK 1/2 kinase activity.…”