Proteolytic degradation patterns of the receptor for advanced glycation end products peptide fragments correlate with their neuroprotective activity in Alzheimer's disease models

Abstract

The receptor for advanced glycation end products (RAGE) plays an essential role in Alzheimer's disease (AD). We previously demonstrated that a fragment (60–76) of RAGE improved the memory of olfactory bulbectomized (OBX) and Tg 5 × FAD mice – animal models of AD. The peptide analog (60–76) with protected N‐ and C‐terminal groups was more active than the free peptide in Tg 5 × FAD mice. This study investigated proteolytic cleavage of the RAGE fragment (60–76) and its C‐ and N‐terminally modified analog by blood serum using HPLC and mass spectrometry. The modified peptide was proteolyzed slower than the free peptide. Degrading the protected analog resulted in shortened fragments with memory‐enhancing effects, whereas the free peptide yielded inactive fragments. After administering the different peptides to OBX mice, their performance in a spatial memory task revealed that the effective dose of the modified peptide was five times lower than that of the free peptide. HPLC and mass spectrometry analysis of the proteolytic products allowed us to clarify the differences in the neuroprotective activity conferred by administering these two peptides to AD animal models. The current study suggests that the modified RAGE fragment is more promising for the development of anti‐AD therapy than its free analog.

Trapping Methylglyoxal by Taxifolin and Its Metabolites in Mice

“…1−4 Increasing evidence indicates that MGO, containing two reactive carbonyl groups, is the leading cause (20 000 times more reactive than glucose) for the formation of advanced glycation end products (AGEs) by binding to and modifying arginine, lysine, and cysteine residues in organisms. 5,6 Over the last few decades, AGEs and MGO have received increasingly more attention and been recognized as pathogenetic mediators in chronic diseases, including diabetes, 7 diabetic complications, 8,9 cardiovascular disease, 10 Alzheimer's disease, 11 and so on. Multiple therapeutic options are available to trap MGO or prevent the formation and accumulation of AGEs or alleviate MGO/AGE-induced chronic diseases.…”

“…Methylglyoxal (MGO) is primarily generated endogenously as a by-product from glycolysis by the nonenzymatic degradation of triose phosphates, such as glyceraldehyde 3-phosphate and dihydroxyacetone-phosphate and exogenously due to autoxidation of sugar, the Maillard reaction, degradation of lipids, and fermentation during food and drink processing. Formation of MGO accounts for only 0.1% of glucotriose flux with a rate of about 125 μmol/kg cell mass per day under physiological conditions. − Increasing evidence indicates that MGO, containing two reactive carbonyl groups, is the leading cause (20 000 times more reactive than glucose) for the formation of advanced glycation end products (AGEs) by binding to and modifying arginine, lysine, and cysteine residues in organisms. , Over the last few decades, AGEs and MGO have received increasingly more attention and been recognized as pathogenetic mediators in chronic diseases, including diabetes, diabetic complications, , cardiovascular disease, Alzheimer’s disease, and so on. Multiple therapeutic options are available to trap MGO or prevent the formation and accumulation of AGEs or alleviate MGO/AGE-induced chronic diseases .…”

RAGE induces physiological activation of NADPH oxidase in neurons and astrocytes and neuroprotection

“…7). However, only peptides P1 and P7 that previously demonstrated the protective activity in vivo [15,16,18] were able to induce ROS production. It was also shown that fragments of the V‐domain of RAGE protect neurons against Aβ induced apoptosis [17] and necrosis (Fig.…”

“…RAGE fragments (Table 1) were derived from the sequences of human RAGE (Q15109 UniProtKB/Swis-sProt). The RAGE peptides were synthesized by solid phase method as described previously [15,18].…”

“…Considering that all the in vitro effects of the synthetic fragment (60-76) were dependent on the RAGE inhibitor, we suggested that this RAGE peptide (60-76) could possibly interact with the same domain of the RAGE receptor. In the present study, we also used the short fragments of peptide (60-76) and the protected analogue of the RAGE peptide (60-76), which was previously discovered to demonstrate a more prolonged effect on the state of the memory of bulbectomized and transgenic mice compared to the free peptide (60-76) [16,18].…”