CONTRIBUTION OF MITOCHONDRIAL DISFUNCTION IN THE DEVELOPMENT OF SPORADIC ALZHEIMER\'S DISEASE: EVIDENCE FROM OXYS RATS

Original title

Authors

Mikhail A. Tyumentsev¹, Natalia A. Muraleva¹, Valentin A. Vavilin², Natalia A. Stefanova¹, Nataliya G. Kolosova¹

Contact information

¹Institute of Cytology and Genetics, Novosibirsk, Russia, Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра.

²Institute of Molecular Biology and Biophysics, Novosibirsk, Russia

Pages

136 - 138

DOI

10.31255/978-5-94797-318-1-136-138

Abstract

Many lines of evidence suggest that decreased mitochondrial function is a hallmark of aging and that mitochondrial dysfunction has a central role in Alzheimer’s disease (AD), the most common type of age-related dementia worldwide, which has no cure. The central role of mitochondria in aging was first proposed by Denham Harman, on the basis of his original theory that aging is caused by the accumulation of damage resulting from reactive oxygen species (ROS). However, recent findings suggest that formation of ROS is neither the primary nor the initial cause of aging. Moreover, transient stress on mitochondria, including mitochondrial ROS (playing a critical role in a number of intra- and extracellular processes), elicits beneficial changes that extend the lifespan. Clearly, mitochondrial function regulates the rate of aging, and mitochondrial dysfunction takes the center stage in the pathophysiology of age-related neurodegenerative disorders, but the underlying mechanisms remain unclear. We explored the role of mitochondrial dysfunction in the development of sporadic late-onset AD, which accounts for ~95% of all disease cases, using senescence-accelerated OXYS rats. This rat model simulates key characteristics of AD including tau protein hyper-phosphorylation, synaptic losses, neuronal cell death, behavioral alterations, and a decrease in cognitive functions on the background of increase in APP levels, enhanced accumulation of Aβ, and formation of amyloid plaques in the brain. The genome of OXYS rats lacking the mutations in the App, Psen1, and Psen2 genes, which are specific for the early form of AD, also speaks in favor of the this model matching the particular criteria of sporadic AD. According to our data, the development and progression of AD-like pathology in OXYS rats may be caused by mitochondrial. Here we summarize our evidence supporting the validity of this assertion.