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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.

We studied the ability of four non-conjugated alpha7-subunit fragments of the nicotinic acetylcholine receptor to induce an immune response and to protect memory in olfactory bulbectomized mice which demonstrate abnormalities similar to Alzheimer's disease (AD). Vaccination only with the alpha7-subunit fragment 173-193 was shown to rescue spatial memory, to restore the level of alpha7 acetylcholine receptors in the cortex, and to prevent an increase in the amyloid-beta (Abeta) level in brain tissue in these animals. Antibodies against the peptide 173-193 were revealed in blood serum and cerebrospinal liquid in the bulbectomized mice. Passive immunization with mouse blood sera containing antibodies to the peptide 173-193 also restored memory in bulbectomized animals. The observed positive effect of both active and passive immunization with the fragment of alpha7-subunit on memory of bulbectomized mice provides a new insight into an anti-AD drug design.