Cellular Stress Response (Hormesis) in Response to Bioactive Nutraceuticals with Relevance to Alzheimer Disease

D. Allan Butterfield, Debra Boyd-Kimball, Tanea T. Reed

Research output: Contribution to journalReview articlepeer-review

3 Scopus citations


Significance: Alzheimer's disease (AD) is the most common form of dementia associated with aging. As the large Baby Boomer population ages, risk of developing AD increases significantly, and this portion of the population will increase significantly over the next several decades. Recent Advances: Research suggests that a delay in the age of onset by 5 years can dramatically decrease both the incidence and cost of AD. In this review, the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in AD is examined in the context of heme oxygenase-1 (HO-1) and biliverdin reductase-A (BVR-A) and the beneficial potential of selected bioactive nutraceuticals. Critical Issues: Nrf2, a transcription factor that binds to enhancer sequences in antioxidant response elements (ARE) of DNA, is significantly decreased in AD brain. Downstream targets of Nrf2 include, among other proteins, HO-1. BVR-A is activated when biliverdin is produced. Both HO-1 and BVR-A also are oxidatively or nitrosatively modified in AD brain and in its earlier stage, amnestic mild cognitive impairment (MCI), contributing to the oxidative stress, altered insulin signaling, and cellular damage observed in the pathogenesis and progression of AD. Bioactive nutraceuticals exhibit anti-inflammatory, antioxidant, and neuroprotective properties and are potential topics of future clinical research. Specifically, ferulic acid ethyl ester, sulforaphane, epigallocatechin-3-gallate, and resveratrol target Nrf2 and have shown potential to delay the progression of AD in animal models and in some studies involving MCI patients. Future Directions: Understanding the regulation of Nrf2 and its downstream targets can potentially elucidate therapeutic options for delaying the progression of AD. Antioxid. Redox Signal. 38, 643-669.

Original languageEnglish
Pages (from-to)643-669
Number of pages27
JournalAntioxidants and Redox Signaling
Issue number7-9
StatePublished - Mar 1 2023

Bibliographical note

Publisher Copyright:
© Copyright 2023, Mary Ann Liebert, Inc., publishers 2023.


  • Alzheimer disease and mild cognitive impairment
  • Nrf2
  • heme oxygenase and biliverdin reductase-A
  • oxidative and nitrosative stress
  • polyphenols

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology


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