ИСТИНА

Alzheimer's disease (AD) is the most prevalent neurodegenerative pathology in the growing population of elderly humans and leads to dementia and death. AD is a complex, age-related neurodegenerative disorder characterized by the impairment of cognitive functions and memory loss. Olfactory bulbectomized mice are particularly promising and appropriate model of nontransgenic, sporadic form of AD. Six weeks after bilateral olfactory bulbectomy (OBX), mice displayed considerable impairment in spatial memory when tested in the Morris's water maze. Decline of learning/memory abilities correlated with increase of β-amyloid in extracts of the neocortex and hippocampus, parts of the brain that are involved in forming new memory and spatial navigation. We have also established that soluble β-amyloid level detected by ELISA was significantly higher in mitochondrial fraction from the neocortex and hippocampus in OBX animals than in sham-operated mice (SO). Loss of neurons as well as its morpho-functional changes such as cytolysis, karyolysis, pycnosis and vacuolization have been revealed in the temporal cortex and hippocampus of OBX mice. Localization of β-amyloid into mitochondria isolated from the neocortex and hippocampus is accompanied with impairments of the electron transport chain and mitochondrial metabolism. We observed a significant decline in the mitochondrial respiratory rate, low value of mitochondrial respiration control ratio (RCR), as well as a decreased activity of the cytochrome c oxidase (COX) and reduced membrane potential. A decline in the COX activity (approx. 35–40%) suggests that a significant deficit in energy generation can lead to catastrophic effects in the functioning of neurons. Defects in mitochondrial function may be a result of toxic effects of β-amyloid via reactive oxygen species leakage promoted by the interaction of β-amyloid with brain mitochondria. These data suggest that early mitochondrial targeted therapeutic interventions may be effective in delaying AD progression in patients.