Effects of Multifunctional Antioxidants on Mitochondrial Dysfunction and Amyloid-β Metal Dyshomeostasis
| Autor: | Karen Blessing, Hiroyoshi Kawada, Tomomi Kiyota, Peter F. Kador, Lee C. Winchester, Theodor A Woolman |
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| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
chemistry.chemical_element Mice Transgenic Zinc Quinolones Biology medicine.disease_cause Rhodamine 123 Antioxidants Tosyl Compounds Mice Neuroblastoma chemistry.chemical_compound Alzheimer Disease Cell Line Tumor medicine Animals Humans Fluorescent Dyes Amyloid beta-Peptides General Neuroscience Clioquinol Neurotoxicity Epithelial Cells General Medicine medicine.disease Mitochondria Staining Disease Models Animal Psychiatry and Mental health Clinical Psychology chemistry Biochemistry Cytoplasm Matrix Metalloproteinase 2 Geriatrics and Gerontology Oxidative stress medicine.drug |
| Zdroj: | Journal of Alzheimer's Disease. 44:297-307 |
| ISSN: | 1875-8908 1387-2877 |
| DOI: | 10.3233/jad-132471 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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