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

• Published in: The Journal of neuroscience Vol. 31; no. 44; pp. 15703 - 15715
• Main Authors: McManus, Meagan J, Murphy, Michael P, Franklin, James L
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 02.11.2011
• Subjects: Age Factors; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Amyloid beta-Peptides - toxicity; Analysis of Variance; Animals; Animals, Newborn; Antioxidants - therapeutic use; Caspases - metabolism; Cell Death - drug effects; Cell Death - genetics; Cells, Cultured; Cerebral Cortex - cytology; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay - methods; Glial Fibrillary Acidic Protein - metabolism; Gliosis - etiology; Gliosis - prevention & control; Glutathione - metabolism; Humans; Lipid Peroxidation - drug effects; Lipid Peroxidation - genetics; Maze Learning - drug effects; Memory Disorders - etiology; Memory Disorders - genetics; Memory Disorders - prevention & control; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - pathology; Neurons - drug effects; Neurons - ultrastructure; Organophosphorus Compounds - therapeutic use; Oxidative Stress - drug effects; Oxidative Stress - genetics; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptide Fragments - toxicity; Retention (Psychology) - drug effects; Rhodamines - metabolism; Space Perception - drug effects; Time Factors; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Ubiquinone - analogs & derivatives; Ubiquinone - therapeutic use
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.0552-11.2011

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.