The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease.

TitleThe mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2011
AuthorsMcManus, MJ, Murphy, MP, Franklin, JL
JournalJ Neurosci
Volume31
Issue44
Pagination15703-15
Date Published2011 Nov 02
ISSN1529-2401
KeywordsAge Factors, Alzheimer Disease, Amyloid beta-Peptides, Analysis of Variance, Animals, Animals, Newborn, Antioxidants, Caspases, Cell Death, Cells, Cultured, Cerebral Cortex, Disease Models, Animal, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Glial Fibrillary Acidic Protein, Gliosis, Glutathione, Humans, Lipid Peroxidation, Maze Learning, Memory Disorders, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Neurons, Organophosphorus Compounds, Oxidative Stress, Peptide Fragments, Retention (Psychology), Rhodamines, Space Perception, Time Factors, Tyrosine, Ubiquinone
Abstract

Considerable evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the progression of Alzheimer's disease (AD). We examined the ability of the novel mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienl-yl) decyl triphenylphosphonium methanesulfonate]) to prevent AD-like pathology in mouse cortical neurons in cell culture and in a triple transgenic mouse model of AD (3xTg-AD). MitoQ attenuated β-amyloid (Aβ)-induced neurotoxicity in cortical neurons and also prevented increased production of reactive species and loss of mitochondrial membrane potential (Δψ(m)) in them. To determine whether the mitochondrial protection conferred by MitoQ was sufficient to prevent the emergence of AD-like neuropathology in vivo, we treated young female 3xTg-AD mice with MitoQ for 5 months and analyzed the effect on the progression of AD-like pathologies. Our results show that MitoQ prevented cognitive decline in these mice as well as oxidative stress, Aβ accumulation, astrogliosis, synaptic loss, and caspase activation in their brains. The work presented herein suggests a central role for mitochondria in neurodegeneration and provides evidence supporting the use of mitochondria-targeted therapeutics in diseases involving oxidative stress and metabolic failure, namely AD.

DOI10.1523/JNEUROSCI.0552-11.2011
Alternate JournalJ. Neurosci.
Citation Key10.1523/JNEUROSCI.0552-11.2011
PubMed ID22049413
PubMed Central IDPMC3334845
Grant ListR01 NS037110-08 / NS / NINDS NIH HHS / United States
R01 NS037110 / NS / NINDS NIH HHS / United States
R01 NS037110-10 / NS / NINDS NIH HHS / United States
NS37110 / NS / NINDS NIH HHS / United States
R29 NS037110 / NS / NINDS NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
R01 NS037110-09 / NS / NINDS NIH HHS / United States
R01 NS037110-07 / NS / NINDS NIH HHS / United States