Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications

Jun Wang,Bing Gong,Tzu-Ying Chen,James Schmeidler,Wei Zhao,Giulio M Pasinetti,Prashant Vempati,Daniel Freire,Elsa M Janle,Mario G Ferruzzi,Lap Ho,Weina Bi,Alice Cheng

doi:10.3389/fnagi.2014.00042

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging and currently has no cure. Its onset and progression are influenced by multiple factors. There is growing consensus that successful treatment will rely on simultaneously targeting multiple pathological features of AD. Polyphenol compounds have many proven health benefits. In this study, we tested the hypothesis that combining three polyphenolic preparations (grape seed extract, resveratrol, and Concord grape juice extract), with different polyphenolic compositions and partially redundant bioactivities, may simultaneously and synergistically mitigate amyloid-β (Aβ) mediated neuropathology and cognitive impairments in a mouse model of AD. We found that administration of the polyphenols in combination did not alter the profile of bioactive polyphenol metabolites in the brain. We also found that combination treatment resulted in better protection against cognitive impairments compared to individual treatments, in J20 AD mice. Electrophysiological examination showed that acute treatment with select brain penetrating polyphenol metabolites, derived from these polyphenols, improved oligomeric Aβ (oAβ)-induced long term potentiation (LTP) deficits in hippocampal slices. Moreover, we found greatly reduced total amyloid content in the brain following combination treatment. Our studies provided experimental evidence that application of polyphenols targeting multiple disease-mechanisms may yield a greater likelihood of therapeutic efficacy.

Highlights

Alzheimer’s disease (AD) is a devastating disorder that strikes 1 in 10 Americans over the age of 65 and almost half of Americans over 85
Consistent with previous findings (Wang et al, 2008; Vingtdeux et al, 2010), all metabolites were found in the plasma and brain following 10-day Comb treatment: catechin and epicatechin from grape seed extracts (GSE) led to the accumulation of PAC glucuronides (Gluc) including catechin-O-β-Gluc, 3 -O-methyl-catechin-O-β-Gluc, epicatechin-O-β-Gluc, and 3 O-methyl-epicatechin-O-β-Gluc; quercetin from juice resulted in the accumulation of quercetin-Gluc, O- methyl quercetin-Gluc, malvidin-glucoside (Glc), petunidin-Glc, delphinidin-Glc, and peonidin-Glc; cyanidin-Glc from juice led to the plasma and brain accumulation of malvidin-3-O-glucoside (Glc), petunidin3-O-Glc, delphinidin-3-O-Glc, peonidin-3-O-Glc, and cyanidin3-O-Glc; resveratrol led to the accumulation of resveratrol and resveratrol Gluc in the brain
Consistent with our previous studies (Wang et al, 2008; Vingtdeux et al, 2010), we found that polyphenolic treatment from all groups were welltolerated; we observed no adverse effects in response to long-term treatments as reflected by normal drinking, eating, grooming behavior, and normal body weight (Figure 1)

Summary

Introduction

Alzheimer’s disease (AD) is a devastating disorder that strikes 1 in 10 Americans over the age of 65 and almost half of Americans over 85. There are approximately 35 million US citizens that are 65 years of age or older who are at risk of developing AD, representing 13% of the population. This number will grow dramatically in the coming decades, reaching 17% of the population by the year 2020. Mounting evidence suggests that polyphenolic compounds, from a variety of diverse sources, are able to improve cognitive function and reduce brain neuropathology in animal models of AD through multiple mechanisms (Rezai-Zadeh et al, 2005; Ringman et al, 2005; Hartman et al, 2006; Vingtdeux et al, 2008; Wang et al, 2008; Thomas et al, 2009; Wang et al, 2009).

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Results

Conclusion