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Published on: September 28, 2019
Effects of multifunctional antioxidants on mitochondrial dysfunction and amyloid-β metal dyshomeostasis
Hiroyoshi Kawada1, Karen Blessing1, Tomomi Kiyota2
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
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(AβPPSwe,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.
Insights
Multifunctional antioxidants (MFAOs) protect mitochondria and reduce amyloid-beta (Aβ) plaques by chelating metals. These findings suggest MFAOs hold therapeutic potential for age-related macular degeneration (AMD) and Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Redox-active metal dyshomeostasis and oxidative stress contribute to mitochondrial dysfunction and amyloid-beta (Aβ) neurotoxicity, implicated in age-related macular degeneration (AMD) and Alzheimer's disease (AD).
- Multifunctional antioxidants (MFAOs) were synthesized as potential therapeutic agents, featuring dual functionality for binding redox-active metals and scavenging free radicals.
Purpose of the Study:
- To investigate the effects of MFAOs on mitochondrial function.
- To determine if MFAOs can reduce amyloid-beta (Aβ) plaque formation and facilitate its degradation.
Main Methods:
- MFAOs were tested in SH-SY5Y and ARPE-19 cell cultures.
- Mitochondrial function was assessed via rhodamine 123 staining after manganese exposure.
- Amyloid-beta (Aβ):zinc complex formation and degradation by MMP-2 were evaluated using Zinquin staining.
- In vivo studies involved orally administering MFAOs to transgenic mice for one year, with Aβ levels measured by ELISA.
Main Results:
- MFAOs did not negatively impact mitochondrial signaling or cytoplasmic zinc levels.
- MFAOs protected cells from manganese-induced mitochondrial dysfunction.
- MFAOs facilitated the degradation of Aβ:zinc complexes by removing zinc, which then appeared as labile cytoplasmic zinc.
- Oral MFAO administration significantly reduced brain Aβ40 and Aβ42 levels in mice.
Conclusions:
- The studied MFAOs exhibit metal-attenuating properties.
- These MFAOs demonstrate therapeutic potential for treating both age-related macular degeneration (AMD) and Alzheimer's disease (AD).
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