Is it all the RAGE? Defining the role of the receptor for advanced glycation end products in Parkinson's disease

Abstract

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non‐transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro‐inflammatory signaling in microglia by binding to amyloid‐β peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain.image

Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study

“…sRAGE was proposed to cause loss of cell surface RAGE/NF-κB-induced pro-inflammatory signaling by preventing binding to ligands, such as HMGB1, AGEs, S100B, β-amyloid, and LPS, among others [ 47 , 48 , 49 , 50 ]. Low levels of sRAGE and high levels of HMGB1 were associated with further pro-inflammatory and pro-oxidant signaling [ 32 ]. In fact, HMGB-1 and sRAGE have been described to correlate inversely in the blood circulation of healthy individuals [ 51 ].…”

“…In fact, HMGB-1 and sRAGE have been described to correlate inversely in the blood circulation of healthy individuals [ 51 ]. As a brain aging hallmark under pathological conditions, reduced levels of sRAGE have been specifically described to be a risk biomarker of neurodegenerative conditions [ 52 ], including mild cognitive impairment, early cognitive decline in type-2 diabetes, AD, and vascular dementia, among others [ 28 , 29 , 30 , 31 , 32 , 53 ]. However, increased sRAGE levels were also described to prevent harmful effects of HMGB1–RAGE interaction as an antioxidant response to the amplification of pathological pro-inflammatory processes and exacerbated oxidative stress conditions [ 31 , 54 ].…”

“…RAGE overactivity contributes to pathological changes in aging and age-related degenerative diseases, such as AD, Parkinson’s disease, and alcohol brain damage [ 14 , 25 ]. Preventing interactions between RAGE and its ligands (e.g., HMGB1) via a soluble decoy isoform of the receptor (soluble RAGE or sRAGE) has recently emerged as an endogenous antioxidant mechanism and a novel potential biomarker for early diagnosis and prognosis of a variety of RAGE-mediated disorders [ 14 , 15 , 17 , 26 , 27 ], including neurodegenerative disorders [ 28 , 29 , 30 , 31 , 32 ] and neuroinflammatory-related diseases [ 33 , 34 , 35 ]. Indeed, chronic alcohol consumption was described to increase sRAGE levels through matrix metalloproteolytic (MMP)-9 activity [ 36 ].…”

Aging and neurodegeneration: From molecular mechanisms to therapeutic interventions

“…Neuroplasticity is the ability of the nervous system to respond to intrinsic and extrinsic stimuli by reorganizing its structure, func- In fact, recent observations strongly suggest that glycation and αsynuclein/RAGE interactions may be crucial in the development of proteinopathy. Based on their findings, the same group Gasparotto et al provides a critical discussion of the role of RAGE in Parkinson's disease (Gasparotto et al, 2023). Vieira et al discuss how the prion protein, the culprit in prion diseases, can also play a role in Parkinson's disease by interacting with and acting as a sensor for αsynuclein, thereby leading to alterations in neuronal function (Vieira et al, 2023).…”

Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation

“…RAGE is a transmembrane receptor in the immunoglobulin superfamily that plays a crucial role in physiological and pathological processes by recognizing and binding to advanced glycation end products (AGEs) and other ligands [ 1 ] Structurally, it has three parts: an extracellular domain for ligand recognition, a transmembrane domain anchoring the receptor in the cell membrane, and an intracellular domain for initiating signaling cascades upon ligand binding [ 2 , 3 ]. RAGE is expressed on the surface of various cell types, including endothelial cells [ 4 ], immune cells [ 5 , 6 ], and neurons [ 7 ].…”