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MITOCHONDRIAL DYSFUNCTIONS IN ANIMAL MODEL OF SPORADIC ALZHEIMER’S DISEASEтезисы доклада
- Авторы: Avetisyan A.V., Simonyan R.A., Aleksandrova I.Ju, Samokhin A.N., Bobkova N.V.
- Сборник: The Ninth International Conference on Bioinformatics of Genome Regulation and Structure\Systems Biology — BGRS\SB-2014, International Symposium "Human genetics" ISHG-2014, Novosibirsk, June 24-25, p. 9
- Тезисы
- Год издания: 2014
- Место издания: Publishing House of the Siberian Branch Russian Academy of Sciences Novosibirsk
- Аннотация: Motivation and Aim: Neurodegenerative Alzheimer’s disease (AD) is the one of leading causes of death in elderly humans. AD is late-onset, age-dependent neurodegeneration, characterized by the progressive decline of memory, cognitive functions, changes in behavior and personality. Mitochondria play special fundamental role in the aging, AD pathology, and β-amyloid induced oxidative damage. Mitochondrial dysfunctions accompanied by oxidative stress could be initiates and contributes to the development and progression of the AD disease. We have observed mitochondrial abnormalities in AD brain tissue, and focused on how mitochondrial may be mediate neurodysfunction and neurodegeneration in the AD brain. Methods and Algorithms: Several studies have suggested that A-induced neurotoxicity in AD could be mediated by oxidative stress and an altered function of respiratory chain associated with oxidative damage These findings have displayed in various human and rodent AD cellular models as well as in triple-transgenic AD mice expressing tau and APP. We investigated a role of mitochondria in AD pathology using sporadic mouse model of AD. Olfactory bulbectomy in mice seems to be a promising and appropriate as a model of nontransgenic, sporadic AD to study neurodegeneration. Results: Six weeks after bilateral olfactory bulbectomy (OBX) mice displayed prominent impairment in spatial memory when tested in the Morris’s water maze. It was shown that β-amyloid was increased in extracts of the neocortex and hippocampus and its level was significantly higher in the OBX animals than in sham-operated mice. The obtained data suggest that bilateral olfactory bulbectomy initiates in the mouse brain pathological processes similar to sporadic AD in location, biochemistry and behavioral manifestation. At the same time mitochondria isolated from the neocortex and hippocampus of OBX mice displayed impairments in respiratory chain (RC) functions, including decline in the mitochondrial respiratory rate and decreased membrane potential, low value of mitochondrial respiration control ratio, reduced activity of the cytochrome c oxidase (COX, complex IV) and increased activity of NADH:quinone oxidoreductase (complex I). We have also established that mitochondrial dysfunctions strictly correlate with the accumulation of soluble β-amyloid into mitochondria from the neocortex and hippocampus of OBX animals. The detected complex IV inhibition could lead to further instability or alterations in the electron flux, and even increased ROS production because of the backup of reduced complexes upstream in the RC. Conclusion and Availability: We have found mitochondrial energy metabolism impairments in neocortex and hippocampus in sporadic type AD. There was direct link between activity of RC complexes and soluble β-amyloid accumulation in mitochondria. New potential drugs able to modulate mitochondrial dynamics and dysfunction could be propose as potential therapeutic drugs that could help mitigating neurodegenerative Alzheimer’s disease.
- Добавил в систему: Аветисян Армине Врежовна