Synthetic Fragment of Receptor for Advanced Glycation End Products Prevents Memory Loss and Protects Brain Neurons in Olfactory Bulbectomized Mice

Article type: Research Article

Authors: Volpina, Olga M.^a | Samokhin, Alexandr N.^b | Koroev, Dmitriy O.^a | Nesterova, Inna V.^b | Volkova, Tatyana D.^a | Medvinskaya, Natalia I.^b | Nekrasov, Pavel V.^b | Tatarnikova, Olga G.^b | Kamynina, Anna V.^{a; *} | Balasanyants, Samson M.^a | Voronina, Tamara A.^c | Kulikov, Alexey M.^d | Bobkova, Natalia V.^b

Affiliations: [a] Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia | [b] Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia | [c] London Neurology and Pain Clinic, London, UK | [d] Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia

Correspondence: [*] Correspondence to: Dr. A. Kamynina, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, st. Miklukho-Maklaya, 16/10, 117997, Moscow, Russia. Tel.: +7 495 3365777; E-mail: aneskaminina@mail.ru.

Abstract: Activation of receptor for advanced glycation end products (RAGE) plays an essential role in the development of Alzheimer’s disease (AD). It is known that the soluble isoform of the receptor binds to ligands and prevents negative effects of the receptor activation. We proposed that peptide fragments from RAGE prevent negative effects of the receptor activation during AD neurodegeneration. We have synthesized peptide fragments from surface-exposed regions of RAGE. Peptides were intranasally administrated into olfactory bulbectomized (OBX) mice, which developed some characteristics similar to AD neurodegeneration. We have found that only insertion of fragment (60–76) prevents the memory of OBX mice. Immunization of OBX mice with peptides showed that again only (60–76) peptide protected the memory of animals. Both intranasal insertion and immunization decreased the amyloid-β (Aβ) level in the brain. Activity of shortened fragments of (60–76) peptide was tested and showed only the (60–70) peptide is responsible for manifestation of activity. Intranasal administration of (60–76) peptide shows most protective effect on morpho-functional characteristics of neurons in the cortex and hippocampal areas. Using Flu-(60–76) peptide, we revealed its penetration in the brain of OBX mice as well as colocalization of Flu-labeled peptide with Aβ in the brain regions in transgenic mice. Flu-(60–76) peptide complex with trimer of Aβ was detected by SDS-PAGE. These data indicate that Aβ can be one of the molecular target of (60–70) peptide. These findings provide a new peptide molecule for design of anti-AD drug and for investigation of RAGE activation ways in progression of AD neurodegeneration.

Keywords: Alzheimer’s disease, amyloid-β , peptides, receptor for advanced glycation end products

DOI: 10.3233/JAD-170483

Journal: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1061-1076, 2018