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

Article type: Research Article

Authors: Reddy, P. Hemachandra^{a; b; c; d; e; f; g; *} | Manczak, Maria^a | Yin, XiangLing^a | Reddy, Arubala P.^{a; h; *}

Affiliations: [a] Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [b] Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [c] Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [d] Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [e] Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [f] Department of Speech, Language and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA | [g] Department of Public Health, Graduate School of Biomedical Sciences, Lubbock, TX, USA | [h] Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

Correspondence: [*] Correspondence to: P. Hemachandra Reddy, PhD, Executive Director and Chief Scientific Officer, Mildred and Shirley L. Garrison Chair in Aging, Professor of Cell Biology and Biochemistry, Neuroscience and Pharmacology and Neurology Departments, Texas Tech University Health Sciences Center, 3601 Fourth Street, MS 9424, 4A 124, Lubbock, TX 79430, USA. E-mail: hemachandra.reddy@ttuhsc.edu and Arubala P. Reddy, PhD, Assistant Professor, Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA. E-mail: Arubala.reddy@ttuhsc.edu.

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.

Keywords: Amyloid-β, mitochondrial biogenesis, mitochondrial division inhibitor 1, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial fission, mitochondria-targeted antioxidant SS31, synergistic protective effects

DOI: 10.3233/JAD-170988

Journal: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1549-1565, 2018