Since the initial isolation and cloning of the receptor for advanced glycation end products (RAGE) in 1992 [1
], it has emerged as a key molecule playing pivotal roles in the pathogenic mechanisms of several major neurological diseases, including Alzheimer’s disease (AD) [3
], stroke [6
], multiple sclerosis [8
], amyotrophic lateral sclerosis [10
] and neurological complications of diabetes [11
], along with many other peripheral diseases, including cancers, diabetic nephropathy, diabetic retinopathy, atherosclerosis, coronary artery disease and rheumatoid arthritis (recently reviewed [12
]). In addition to being a pattern-recognition receptor for advanced glycation end products (AGEs), RAGE binds a number of other ligands [15
]. Prominent among these is the amyloid β (Aβ) peptide, which is the central player in AD pathogenic mechanisms [18
]. RAGE-associated diseases share common features of the sustained and increased presence of different RAGE ligands in association with disease pathology and the common involvement of vascular dysfunction. Ligand binding activates cell surface-bound full-length RAGE (flRAGE) leading to inflammatory signaling, which also involves increased expression of RAGE. Different cellular signaling pathways are activated by RAGE ligation, which will be discussed in detail in this review. The central feature is that the RAGE
gene promoter contains NF-κB and SP1 transcription elements that respond to proinflammatory cellular signaling by increased expression of RAGE [19
]. The end result of this is that cell-surface RAGE receptor and ligand interaction sets up a positive feedback mechanism that can rapidly accelerate disease progression.
By contrast, soluble forms of RAGE provide significant inhibition to these positive feedback mechanisms, since these forms of RAGE contain functional ligand-binding domains but lack the cellular signaling domains. Their suggested mechanism of action is to bind to RAGE ligands in the extracellular environment, thus preventing the ligand interaction with flRAGE. The therapeutic potential of soluble forms of the RAGE protein was demonstrated in animal model studies of atherosclerosis, diabetes and systemic amyloidosis; all of these studies demonstrated that administration of recombinant soluble RAGE (sRAGE) protein containing the ligand-binding domain had significant disease-modifying effects [20
The discovery of soluble forms of RAGE endogenously present under physiological conditions has provided insight into the protective roles that RAGE molecules could play in these diseases. Over the last few years, as many different alternative forms of RAGE have been identified, the lack of systematic nomenclature has led to a confusing array of different names. Recently, Hudson and colleagues have analyzed 20 RAGE transcripts in lung or aortic smooth muscle cells [24
]. Based on their data, they suggested a new unifying naming system for the various RAGE isoforms [24
]. As the physiological significance of many of these isoforms is not known, this article will focus on the properties of flRAGE, and the soluble forms of RAGE, generated by alternative splicing (termed endogenous-secretory RAGE [esRAGE]) or enzymatically-cleaved RAGE (ecRAGE) [24
]. In studies discussed in this review, measurements of sRAGE refer to a pool containing esRAGE and ecRAGE. The carboxyl terminal sequences differ between ecRAGE and esRAGE [28
]. Ligand binding with esRAGE and ecRAGE avoids the adverse consequences of activating signal transduction pathways that can increase inflammation and cellular perturbation. As these soluble forms of RAGE compete for ligands with the flRAGE, they can be considered protective.
We will focus on recent findings of how different forms of RAGE are involved with different aspects of AD pathobiology, and whether they present therapeutic targets for disease modification.