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

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.

Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer’s Disease and Parkinson’s Disease

“…Olfactory-bulbectomized (OBX) animals develop symptoms similar to those observed in AD. They display learning and memory impairment and cholinergic neurodedegeneration in the central nervous system [16,17,18]. We examined whether nobiletin exerts beneficial effects against the features of AD in OBX mice [19,20].…”

Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer’s Disease Development

“…Specifically, a cyclic peptide corresponding to the Aβ binding domain of the transthyretin, a stable homotetrameric transport protein circulating in blood and cerebrospinal fluid, has been shown to be neuroprotective against Aβ toxicity in vitro and suppress Aβ aggregation [ 164 , 165 ]. One more example of such decoy peptides could be represented by a peptide corresponding to the 60–76 sequence from the V-domain of the receptor for advanced glycation end products (RAGE) [ 166 , 167 ]. Its therapeutic efficacy is likely to be related to its competition with the RAGE V-domain for binding to Aβ and involvement in Aβ clearance in the brain.…”

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

“…Previously, we administered the fragment (60–76) of the V‐domain of RAGE to OBX mice and observed improvements in their performance in spatial memory tasks (Volpina et al, 2018); these mice are common models of depression (Leonard & Tuite, 1981; Song & Leonard, 2005). OBX mice are good models for AD because they develop memory impairment, cholinergic deficiency, and high levels of brain Аβ (Aleksandrova et al, 2004; Bobkova et al, 2016; Hozumi et al, 2003; Kamynina et al, 2010; Nakajima et al, 2007; Yamamoto et al, 1997; Yehuda & Rabinovitz, 2015).…”

“…Under intranasal administration, the peptide (60–76) penetrated the blood–brain barrier, reduced cerebral Aβ, and improved neuronal morphology and mitochondrial function in OBX mice (Avetisyan et al, 2020; Volpina et al, 2018). We co‐cultured primary neurons and astrocytes from the hippocampus and cortex of rat brains, treated them with peptide (60–76), and observed a reduction in Aβ 1–42 toxicity compared to that without treatment.…”