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J Biol Chem. 2019 Feb 22;294(8):2714-2731. doi: 10.1074/jbc.RA118.004280. Epub 2018 Dec 18.

Combined treatment with the phenolics (-)-epigallocatechin-3-gallate and ferulic acid improves cognition and reduces Alzheimer-like pathology in mice.

Author information

1
From the Departments of Biomedical Sciences and t_mori@saitama-med.ac.jp.
2
Pathology, Saitama Medical Center and University, Kawagoe, Saitama 350-8550, Japan.
3
From the Departments of Biomedical Sciences and.
4
the Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, Morsoni College of Medicine, University of South Florida, Tampa, Florida 33613.
5
the Immuno-Biological Laboratories Co., Ltd., Fujioka, Gunma 375-0005, Japan, and.
6
the Zilkha Neurogenetic Institute, Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-2821 ttown@usc.edu.

Abstract

"Nutraceuticals" are well-tolerated natural dietary compounds with drug-like properties that make them attractive as Alzheimer's disease (AD) therapeutics. Combination therapy for AD has garnered attention following a recent National Institute on Aging mandate, but this approach has not yet been fully validated. In this report, we combined the two most promising nutraceuticals with complementary anti-amyloidogenic properties: the plant-derived phenolics (-)-epigallocatechin-3-gallate (EGCG, an α-secretase activator) and ferulic acid (FA, a β-secretase modulator). We used transgenic mice expressing mutant human amyloid β-protein precursor and presenilin 1 (APP/PS1) to model cerebral amyloidosis. At 12 months of age, we orally administered EGCG and/or FA (30 mg/kg each) or vehicle once daily for 3 months. At 15 months, combined EGCG-FA treatment reversed cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks. Moreover, EGCG- and FA-treated APP/PS1 mice exhibited amelioration of brain parenchymal and cerebral vascular β-amyloid deposits and decreased abundance of amyloid β-proteins compared with either EGCG or FA single treatment. Combined treatment elevated nonamyloidogenic soluble APP-α and α-secretase candidate and down-regulated amyloidogenic soluble APP-β, β-C-terminal APP fragment, and β-secretase protein expression, providing evidence for a shift toward nonamyloidogenic APP processing. Additional beneficial co-treatment effects included amelioration of neuroinflammation, oxidative stress, and synaptotoxicity. Our findings offer preclinical evidence that combined treatment with EGCG and FA is a promising AD therapeutic approach.

KEYWORDS:

Alzheimer disease; flavonoid; amyloid precursor protein (APP); amyloid-beta (AB); secretase; transgenic mice; neuroinflammation; oxidative stress; nonamyloidogenic; phenol; plant; polyphenol

PMID:
30563837
PMCID:
PMC6393618
[Available on 2020-02-22]
DOI:
10.1074/jbc.RA118.004280

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