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- (A) 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 A 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 A:Zn complex formation were evaluated with Zinquin staining and the ability of the A:Zn complex to be degraded by matrix metalloproteinase-2 (MMP-2). The ability of MFAOs to reduce A plaque in the brain was determined by orally feeding MFAO for one year to B6;129-Psen1tm1Mpm Tg(AβPPSwe,tauP301L) 1Lfa/Mmjax transgenic mice. A levels were determined by ELISA. Results: MFAOs neither adversely affected mitochondrial signaling nor labile cytoplasmic zinc levels. MFAOs protected cells against Mn 2+ -induced mitochondrial dysfunction. MFAOs also removed zinc from the A:Zn complex so that A 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 A40 and A42 isoforms of A. Conclusion: These studies demonstrate that these MFAOs have metal attenuating properties with therapeutic potential in the treatment of both AMD and AD.