Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer's Disease.

Abstract

The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer's disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant AβPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-β (Aβ) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells. We found significantly reduced levels of Aβ40 and Aβ42 in mutant AβPP cells treated with SS31, Mdivi1, and SS31+Mdivi1, and the reduction of Aβ42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunction is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treated cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons.

• Authors: P Hemachandra Reddy, Maria Manczak, XiangLing Yin, Arubala P Reddy
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 62 Issue 4 Pg. 1549-1565 ( 2018) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 29400667 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• DNA, Mitochondrial
• Neuroprotective Agents
• Oligopeptides
• Peptide Fragments
• Quinazolinones
• amyloid beta-protein (1-42)
• arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• DNA, Mitochondrial (metabolism)
• Mice
• Mitochondria (drug effects, metabolism)
• Mutation
• Neuroprotective Agents (pharmacology)
• Oligopeptides (pharmacology)
• Peptide Fragments (metabolism)
• Quinazolinones (pharmacology)