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INHIBITION OF MITOCHONDRIAL FISSION AMELIORATES THE PATHOGENESIS OF ALZHEIMER'S DISEASE

      Background

      Alzheimer’s disease (AD) is an age-related disorder characterized by deposition of neurotoxic form of beta-amyloid (Aβ) and degeneration of neurons. In the brain, accumulation of Aβ in the mitochondrial compartment has a responsible role in impairing mitochondrial physiological functions. Impaired regulation of mitochondrial dynamics, which shifts the balance towards fission, is associated with neuronal death in age-related neurodegenerative diseases, such as AD.

      Methods

      We investigated the effect of inhibition of mitochondial fission protein Drp1 (dynamin-related prtein 1) by Mdivi-1 in AD mice and neuronal cells.

      Results

      Mdivi-1 prevents learning and memory impairments of the APP/PS1 transgenic mice. Mitochondrial length is increased in Mdivi-1 treated primary neuronal hippocampal cells. Inhibitory effects of Mdivi-1 on Aβ-induced activation of reactive oxygen species (ROS) in brain of APP/PS1 mice. BACE1 expression are down-regulated in the brains of Mdivi-1(40mg/kg) treated APP/PS1 mice. Administration of Mdivi-1significantly reduces neuritic plaques formation and Aβ production in APP/PS1 mice.

      Conclusions

      Mdivi-1 deficiency results in protection against Aβ-induced brain damage by mitoch-ondrial dysfunction and neuronal death. Mdivi-1 improved cognitive performance of AD mice, in addition to decreased neuritic plaques formation and Aβ production and suppressed BACE1 expression and mitochondrial dysfunction. These results indicate that inhibition of mitochondrial fission can be a therapeutic approach for AD.