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

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.