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MECHANISM OF PATHOLOGICAL ACTION OF AMYLOID-BETA ON NEURONAL MITOCHONDRIA IN ALZHEIMER'S TYPE NEURODEGENERATION, THERAPEUTIC EFFECT OF THE SYNTHETIC FRAGMENT OF RAGEстатья
- Авторы: Avetisyan Armine V., Simonyan Ruben A., Zinovkin Roman A., Balasanyants Samson M., Koroev Dmitriy O., Volpina Olga M., Bobkova Natalia V.
- Сборник: Neuroscience for Medicine and Psychology
- Том: 1
- Год издания: 2020
- Место издания: LLC MAKS Press Москва
- Первая страница: 52
- Последняя страница: 53
- DOI: 10.29003/m902.sudak.ns2020-16/52
- Аннотация: The sporadic Alzheimer's disease (AD) is the most common neurodegenerative pathology of the adult brain. Dysfunction of the brain mitochondria is detected already in the early stages of the disease, preceding the onset of clinical symptoms and deposition of amyloid plaques. The brain has extreme metabolic requirements, and perturbations or dysfunctions in energy metabolism and ATP generation are often implicated in numerous diseases, including neurodegenerative disorders. The drug development for effective treatment of AD iscomplicated by the not fully understanding of the causes and biochemical processes of pathogenesis. We have shown functional abnormalities in mitochondrial metabolism, a decrease in the activity of respiratory complexes I and IV, an increase of reactive oxygen species in the brain of olfactory bulbectomized (OBX) mice, well known as the animal model of sporadic AD. The accumulation of the soluble amyloid-beta (Abeta 1-40) was detected in the mitochondria in the neocortex and hippocampus of the OBX mice, causing mitochondrialimpairments and inhibition of respiratory chain activity, resulting in neuronal death in the corresponding areas of the brain. The cytoplasmic membrane receptor for advanced glycation end products, or RAGE, is known to play an important role in the pathogenesis of AD by mediating the influx of free circulating Abeta into the brain across the blood-brain barrier. RAGE binds several ligands including Abeta monomers and oligomers, that activate the receptor and intracellular signaling. Microglial RAGE activation by Abeta triggers intracellular signaling cascades leading to inflammation, mitochondrial dysfunction, oxidative stress and neuronal injury. We synthesized a peptide fragment (60-76) having an amino acid sequence identical to the exposed nonstructural loop of the RAGE V-domain. The intranasal administration of this peptide fragment for 3 weeks improved the spatial memory of OBX mice, reduced the level of brain Abeta, restored the activity of the respiratory chain complexes I and IV in mitochondria, and decreased the level of oxidative stress. In vitro measurements showed that the fluorescein-labeled analog Flu- (60-76) binds to Abeta with high affinity (nanomolar Kd), indicating the direct interaction of the RAGE fragment (60-76) with Abeta. Peptide (60-76) may act as a high affinity Aβ decoy peptide in vivo, protecting the brain from the toxic action of free Abeta in OBX mice.The study was supported by Russian Foundation for Basic Research (RFBR 19-04-00624; 19-015-00064).
- Добавил в систему: Аветисян Армине Врежовна