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

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.

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

“…No formal assessment has been made in relation to changes in sphingolipid levels in neurons after treatment with resveratrol. Nevertheless, neuroprotection has been consistently observed at <50 µM of resveratrol, which is lower than the concentration required to inhibit SK1 activity (K i = 160 ± 40 μM) and to induce apoptosis (Capiralla et al 2012;Chen et al 2005;Feng et al 2013;Lim et al 2012a;Marambaud et al 2005;Wang et al 2014). Therefore, low micromolar concentrations of resveratrol might mediate protection via a mechanism that does not involve changes in sphingolipid levels.…”

Protective effects of berry polyphenols against age-related cognitive impairment

“…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]. According to a recent report, chronic resveratrol administration leads to decreases in the ratio of soluble A␤42/A␤40 (−42%) and in the concentration of insoluble human tau (−93%) in the parietotemporal cortex of 18-month-old mice in a triple-transgenic model of AD [187].…”

Slowing the progression of Alzheimer’s disease; what works?

“…Other genetic variations identified by genome-wide association studies have been found to influence the risk of developing AD through their interaction with protein degradation and transport, immune activity, lipid transport and metabolism, and mitochondrial function (Tosto and Reitz 2013). Their influence upon rate of progression of AD is now beginning to be explored (Wang et al 2014). …”