Effects of multifunctional antioxidants on mitochondrial dysfunction and amyloid-β metal dyshomeostasis

Hiroyoshi Kawada, Karen Blessing, Tomomi Kiyota, Theodor Woolman, Lee Winchester, Peter F. Kador

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Background: Redox-active metal dyshomeostasis and oxidative stress are associated with mitochondrial dysfunction and amyloid-β (Aβ) neurotoxicity that are linked to both the development of age-related macular degeneration (AMD) and Alzheimer's disease (AD). As potential therapeutic agents, orally active multifunctional antioxidants (MFAOs) possessing two independent functional groups capable of binding redox-active metals and scavenging free radicals have been synthesized. Objective: To determine whether MFAOs affect mitochondrial function and reduce the presence of Aβ plaque formation. Methods: The MFAOs were evaluated in cultured SH-SY5Y cells and ARPE-19 cells. MFAO effects on mitochondrial function were investigated using rhodamine 123 staining after 2 hour exposure to MnCl2. MFAO effects on Aβ:Zn complex formation were evaluated with Zinquin staining and the ability of the Aβ:Zn complex to be degraded by matrix metalloproteinase-2 (MMP-2). The ability of MFAOs to reduce Aβ plaque in the brain was determined by orally feeding MFAO for one year to B6;129-Psen1tm1Mpm Tg(AßPPSwe, tauP301L) 1Lfa/Mmjax transgenic mice. Aβ levels were determined by ELISA. Results: MFAOs neither adversely affected mitochondrial signaling nor labile cytoplasmic zinc levels. MFAOs protected cells against Mn2+-induced mitochondrial dysfunction. MFAOs also removed zinc from the Aβ:Zn complex so that Aβ plaque could be degraded by MMP-2. Zinquin staining indicated that the removed zinc was present in the cytoplasm as labile zinc. Orally administered MFAOs reduced the brain levels of both Aβ40 and Aβ42 isoforms of Aβ. Conclusion: These studies demonstrate that these MFAOs have metal attenuating properties with therapeutic potential in the treatment of both AMD and AD.

Original languageEnglish (US)
Pages (from-to)297-307
Number of pages11
JournalJournal of Alzheimer's Disease
Volume44
Issue number1
DOIs
StatePublished - 2015

Keywords

  • Age-related macular degeneration
  • Alzheimer's disease
  • Amyloid-β
  • Clioquinol
  • JAX transgenic Alzheimer mouse
  • Mitochondrial dysfunction
  • Multifunctional antioxidants

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'Effects of multifunctional antioxidants on mitochondrial dysfunction and amyloid-β metal dyshomeostasis'. Together they form a unique fingerprint.

  • Cite this