Phenolic Compounds Prevent Alzheimer’s Pathology through Different Effects on the Amyloid-β Aggregation Pathway

Abstract

Inhibition of amyloid-␤ (A␤) aggregation is an attractive therapeutic strategy for Alzheimer's disease (AD). Certain phenolic compounds have been reported to have anti-A␤ aggregation effects in vitro.This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA-and RA-treated groups, A␤ deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group , the level of Trisbuffered saline (TBS)-soluble A␤ monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was decreased (P < 0.001). However, in the NDGA-treated group, the abundance of A11-positive oligomers was increased (P < 0.05) without any change in the levels of TBS-soluble or TBS-insoluble A␤. In the curcumin-and myricetin-treated groups, changes in the A␤ profile were similar to those in the RA-treated group, but A␤ plaque deposition was not significantly decreased. In the ferulic acid-treated group, there was no significant difference in the A␤ profile. These results showed that oral administration of phenolic compounds prevented the development of AD pathology by affecting different A␤ aggregation pathways in vivo. Clinical trials with these compounds are necessary to confirm the anti-AD effects and safety in humans. Alzheimer's disease (AD) is the most common form of dementia, resulting in deterioration of cognitive function and behavioral changes.1 One of the pathological hallmarks of AD is extracellular deposits of aggregated amyloid-␤ protein (A␤) in the brain parenchyma (senile plaques) and cerebral blood vessels (cerebral amyloid angiopathy (CAA)).1 Deposition of high levels of fibrillar A␤ in the AD brain is associated with loss of synapses, impairment of neuronal functions, and loss of neurons. 2-5A␤ was sequenced from meningeal vessels and senile plaques of AD patients and individuals with Down's syndrome.6 -8 The subsequent cloning of the gene encoding the ␤-amyloid precursor protein and its localization to chromosome 21, 9 -12 coupled with the earlier recognition that trisomy 21 (Down's syndrome) invariably leads to the neuropathology of AD, 13 set the stage for the proposal that A␤ accumulation is the primary event in AD pathogenesis. In addition, certain mutations associated with familial AD have been identified within or near the A␤ region of the coding sequence of gene of the amyloid precursor proteins, 14,15 presenilin-1 and presenilin-2, 16 which alter amyloid precursor protein metabolism through a direct effect on ␥-secretase. 17,18 These findings set the stage for the proposal that A␤ aggregation is the primary event in AD pathogenesis and leading to the proposal that anti-A␤ aggregation is a strategy for AD therapy.

Protective Effects of Ferulic Acid in Amyloid Precursor Protein Plus Presenilin-1 Transgenic Mouse Model of Alzheimer Disease

“…18) If each mouse is assumed to take about 3-4 g of chow (containing 0.5% ferulic acid) per day, the ferulic acid dose is around 500-667 mg/kg/d, 18) which about 95-125 fold higher than the dose of 5.3 mg/kg/d used in the present study. Thus, the reason for the lack of ferulic acid effect on Aβ diposition in Hamaguchi et al 18) most probably could be due to the use of an inappropriately high dose. It is to be noted that curcumin, an analogue of ferulic acid, has also been reported to decrease amyloid deposition and Il-1β levels in the brain of APP transgenic mice at a low dose but not at a high dose.…”

“…Recently, it has been reported that chronic administration of ferulic acid did not affect Aβ diposition in the brain of APP/PS1 mice. 18) These mice were fed with chow containing 0.5% ferulic acid for 1 year (from the age of 4 months to 14 months). 18) If each mouse is assumed to take about 3-4 g of chow (containing 0.5% ferulic acid) per day, the ferulic acid dose is around 500-667 mg/kg/d, 18) which about 95-125 fold higher than the dose of 5.3 mg/kg/d used in the present study.…”

“…18) These mice were fed with chow containing 0.5% ferulic acid for 1 year (from the age of 4 months to 14 months). 18) If each mouse is assumed to take about 3-4 g of chow (containing 0.5% ferulic acid) per day, the ferulic acid dose is around 500-667 mg/kg/d, 18) which about 95-125 fold higher than the dose of 5.3 mg/kg/d used in the present study. Thus, the reason for the lack of ferulic acid effect on Aβ diposition in Hamaguchi et al 18) most probably could be due to the use of an inappropriately high dose.…”

Wine consumption, cognitive function and dementias – A relationship?

“…Wine-derived phenolic compounds, and particularly resveratrol, have been shown be cerebro-or neuroprotective in various models, in vitro and in vivo, and potential mechanisms have been proposed. Data from similar studies using different varieties of red wines with different profiles of phenolic compounds, as well as studies comparing different phenolic compounds, suggest that the individual classes of phenolic compounds may exhibit differential effects in the brain [98,99]. From Scholey et al (2014), the consumption of 100 mL of red wine with a relatively low concentration of resveratrol resulted in better performance by elderly subjects during Series Threes of Cognitive Demand Battery tests, compared with consumption of that same wine enriched with 100 mg resveratrol, while the resveratrol-enriched red wine resulted in better performance during Serial Sevens [155].…”

Effect of natural antioxidants on the aggregation and disaggregation of beta-amyloid

“…Additionally, the use of compounds or extracts inhibiting Aβ aggregation is considered a good approach to the therapy and prevention of AD. For example, flavonoids such as myricetin, quercetin, and kaempferol inhibited Aβ aggregation (exhibited antiamyloidogenic activities) [12][13][14]. Additionally, rosmarinic acid and curcumin are other compounds that inhibit Aβ aggregation efficiently [15,16].…”