mitoquinone and Memory-Disorders

Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1(9-36)(amide) possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)(amide) prevented impaired long-term potentiation (LTP) and enhanced long-term depression induced by exogenous amyloid β peptide Aβ((1-42)). Similarly, hippocampal LTP impairments in amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice that model Alzheimer's disease (AD) were prevented by GLP-1(9-36)(amide). In addition, treatment of APP/PS1 mice with GLP-1(9-36)(amide) at an age at which they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1(9-36)(amide) reduced elevated levels of mitochondrial-derived reactive oxygen species and restored dysregulated Akt-glycogen synthase kinase-3β signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)(amide) treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Association Learning; CA3 Region, Hippocampal; Disease Models, Animal; Drug Evaluation, Preclinical; Excitatory Postsynaptic Potentials; Fear; Female; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Memory Disorders; Mice; Mice, Transgenic; Mitochondria; Neuronal Plasticity; Nootropic Agents; Organophosphorus Compounds; Peptide Fragments; Peptides; Presenilin-1; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Ubiquinone

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.

Topics: Age 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