A Synthetic Fragment of the Receptor for Glycation End Products and Its Analogue Improve Memory in Transgenic Alzheimer’s Disease Mouse Model

Abstract

The membrane receptor for advanced glycation endproducts (RAGE) is involved in the development of a number of pathological conditions, including Alzheimer’s disease (AD), in which the receptor overexpression in brain cells and its increasing activity is observed. We have previously shown that the synthetic fragment RAGE (60–76), administered intranasally, could prevent the disturbance of the spatial memory of olfactory bulbectomized mice, that develop features of AD. We suggested that N-terminal amino function of the peptide protected with acetic group and C-terminal carboxyl group replaced with amide, would increase the stability of this peptide in in vivo experiments, and this protected peptide would show higher activity compared to the original free one. In the current study the protected peptide analog Ac-(60–76)-NH₂ was synthesized. The activity of the peptide (60–76) and its protected analog has studied in transgenic 5xFAD mice, which represent a generally accepted model of AD. The memory testing was performed in the Morris water maze. It was shown that intranasal administration of these peptides to transgenic 5xFAD mice for two months preserved the spatial memory of animals, and both peptides exhibited the same ability to prevent the spatial memory. The difference in the activity of the tested peptides was revealed 7 days after drug administration had been over, and only animals, previously received the modified peptide Ac-(60–76)-NH₂, showed the ability to find the Morris water maze learning sector. The animals received the peptide (60–76) lost their ability to find the learning sector after 7 days and were completely disoriented. The data obtained allow us to conclude that the modified fragment (60–76) with protected N- and C-terminal functional groups has a more pronounced and long lasting protective effect compared to the free peptide (60–76). Thus, Ac-(60–76)-NH₂ is a promising candidate for development of the drug for the treatment of Alzheimer’s disease.