Role of RAGE in Alzheimer’s Disease

Abstract

Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

“…Advanced glycation end products and its soluble receptor have been implicated in the pathogenesis of AD [52,53]. Although not statistically significant, levels of the soluble form of RAGE (sRAGE) were decreased 48% in African Americans and indicated a medium effect size.…”

“…Although not statistically significant, levels of the soluble form of RAGE (sRAGE) were decreased 48% in African Americans and indicated a medium effect size. sRAGE lacks the transmembrane domain and intracellular tail and is thought to act as an extracellular decoy by sequestering RAGE ligands [47,[53][54][55]. That sequestration can then prevent the activation of RAGE and its downstream pathological signaling effects.…”

Plasma Levels of Pentosidine, Carboxymethyl-Lysine, Soluble Receptor for Advanced Glycation End Products, and Metabolic Syndrome: The Metformin Effect

“…Previous studies have confirmed that interaction between AGEs and RAGE activates the generation of oxidative stress and production of proinflammatory cytokines in various types of cells that have been implicated in metabolic and many other disease statuses [13–16]. Furthermore, Monden et al have shown that RAGE affects adipocyte hypertrophy and insulin sensitivity in mice [17].…”

Targeting neuroinflammation in Alzheimer’s disease

“…This is possible because of the presence of proinflammatory receptors on their surface. Microglia is able to identify and bind Aβ oligomers and fibrils and the amyloid precursor protein (APP)57 through a large number of receptors, including scavenger receptor class A type 1, MARCO, scavenger receptor class B member 1, CD36, and the receptor for advanced glycation end product,58,59 G protein-coupled receptors formyl peptide receptor 2 60 and chemokine-like receptor 1,61 toll-like receptors (TLRs) TLR2,62 TLR4, and the CD14 coreceptor, and α6β1 integrin 63. The outcome of the bond between Aβ and these receptors is the production of inflammatory mediators such as cytokines (interleukin [IL]-1α, IL-1β, IL-6, IL-8, IL-12, IL-18, and IL-23, interferon (IFN)-γ, tumor necrosis factor [TNF]-α, and granulocyte-macrophage colony-stimulating factor [GM-CSF]),64,65 chemokines (monocyte chemotactic protein 1 (MCP1), MCP-113, fractalkine),66,67 chemoattractant proteins, prostaglandins, complement factors, thromboxanes, pentraxins, NO, reactive oxygen species, leukotrienes, proteases, protease inhibitors, adhesion molecules (interaction between CD40-CD40 ligand CD40L),68 coagulation factors, and C-reactive protein, most of which are detectable in AD animal and/or in the brain or cerebrospinal fluid of AD patients 25,69,70.…”