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

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


"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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / physiology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antioxidants / pharmacology
  • Behavior, Animal
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Coumaric Acids / pharmacology*
  • Disease Models, Animal*
  • Drug Therapy, Combination
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Presenilin-1 / physiology*


  • Amyloid beta-Protein Precursor
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antioxidants
  • Coumaric Acids
  • Presenilin-1
  • Catechin
  • ferulic acid
  • epigallocatechin gallate