Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons.

TitleMitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons.
Publication TypeJournal Article
Year of Publication2010
AuthorsManczak, M, Mao, P, Calkins, MJ, Cornea, A, Reddy, AP, Murphy, MP, Szeto, HH, Park, B, P Reddy, H
JournalJ Alzheimers Dis
Volume20 Suppl 2
PaginationS609-31
Date Published2010
ISSN1875-8908
KeywordsAdenosine Triphosphate, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Antioxidants, Cell Line, Transformed, Cell Survival, Disease Models, Animal, Drug Interactions, Electron Transport Complex IV, Gene Expression Regulation, Humans, Hydrogen Peroxide, Lipid Peroxidation, Membrane Potential, Mitochondrial, Mice, Mice, Transgenic, Microscopy, Electron, Transmission, Mitochondria, Mitochondrial Proteins, Neurons, Peptide Fragments, Peroxiredoxins, RNA, Messenger
Abstract

The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants, MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model (Tg2576 line) of Alzheimer's disease (AD) and on mouse neuroblastoma (N2a) cells incubated with the amyloid-beta (Abeta) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Abeta. In N2a cells only incubated with the Abeta, we found increased expressions of mitochondrial fission genes and decreased expression of fusion genes and also decreased expression of peroxiredoxins. Electron microscopy of the N2a cells incubated with Abeta revealed a significantly increased number of mitochondria, indicating that Abeta fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Abeta-incubated N2a cells, indicating that Abeta affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Abeta, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid-beta precursor protein transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that MitoQ and SS31 prevent Abeta toxicity, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.

DOI10.3233/JAD-2010-100564
Alternate JournalJ. Alzheimers Dis.
Citation Key10.3233/JAD-2010-100564
PubMed ID20463406
PubMed Central IDPMC3072711
Grant ListAG026051 / AG / NIA NIH HHS / United States
AG028072 / AG / NIA NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
R01 AG028072 / AG / NIA NIH HHS / United States
R01 AG028072-03 / AG / NIA NIH HHS / United States
RR00163 / RR / NCRR NIH HHS / United States