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Review
. 2023 May 17:16:1155175.
doi: 10.3389/fnmol.2023.1155175. eCollection 2023.

AGE-RAGE axis culminates into multiple pathogenic processes: a central road to neurodegeneration

Reshmee Bhattacharya  1 , Mohammad Rizwan Alam  2 , Mohammad Azhar Kamal  3 , Kyung Jin Seo  2 , Laishram Rajendrakumar Singh  1
Affiliations
Review

AGE-RAGE axis culminates into multiple pathogenic processes: a central road to neurodegeneration

Reshmee Bhattacharya et al. Front Mol Neurosci. .

Abstract

Advanced glycation end-products (AGEs; e.g., glyoxal, methylglyoxal or carboxymethyl-lysine) are heterogenous group of toxic compounds synthesized in the body through both exogenous and endogenous pathways. AGEs are known to covalently modify proteins bringing about loss of functional alteration in the proteins. AGEs also interact with their receptor, receptor for AGE (RAGE) and such interactions influence different biological processes including oxidative stress and apoptosis. Previously, AGE-RAGE axis has long been considered to be the maligning factor for various human diseases including, diabetes, obesity, cardiovascular, aging, etc. Recent developments have revealed the involvement of AGE-RAGE axis in different pathological consequences associated with the onset of neurodegeneration including, disruption of blood brain barrier, neuroinflammation, remodeling of extracellular matrix, dysregulation of polyol pathway and antioxidant enzymes, etc. In the present article, we attempted to describe a new avenue that AGE-RAGE axis culminates to different pathological consequences in brain and therefore, is a central instigating component to several neurodegenerative diseases (NGDs). We also invoke that specific inhibitors of TIR domains of TLR or RAGE receptors are crucial molecules for the therapeutic intervention of NGDs. Clinical perspectives have also been appropriately discussed.

Keywords: AGE; RAGE; Velcade; glycation; neurodegeneration.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Fates of Advanced glycation end-product (AGE)-induced glycation of different proteins.
Figure 2
Figure 2
Schematic representation of AGE–RAGE signaling pathways. Binding of AGE to RAGE results in its dimerization followed by recruitment of adaptor protein (mDia1) to the cytoplasmic domain of RAGE. Recruitment of mDia1 activates four major signaling pathways. (A), mDia1 recruits JAK which then phosphorylates STAT to form dimers. Activated STAT then translocate to the nucleus, enabling expression of various cytokine-responsive genes, leading to inflammatory response. (B) Binding of mDia1 may stimulate switching of GDP-bound cdc 42 to its active GTP-bound state. Activated cdc42 further activates Rac-1 which phosphorylates downstream MAPKs (JNK and p38). Phosphorylation of JNK and p38 results in the activation of AP-1 and NF-κB transcription factors. (C) mDia1 again may recruit SOS, wherein it activates RAS by exchanging GDP to GTP. GTP-bound RAS further activates RAF finally initiating phosphorylation cascade by activating MAPKs (ERK1/2, p38 and JNK). These MAPKs translocate to the nucleus and activates AP-1 transcription factor. ERK/p38/JNK may also activate NF-κB in the cytoplasm, regulating various genes involved in inflammatory response. (D) mDia1 may also stimulate activation of PI3K protein. Activated PI3K further phosphorylates PIP2 to form PIP3, which in turn phosphorylates and activates AKT. Once activated, AKT further stimulate NF-κB which moves to the nucleus and regulates transcription of several genes. Activated RAGE may also bind to other adaptor proteins (MyD88 and TIRAP) initiating a phosphorylation event ultimately leading to NF-κB activation (see text for detail explanation).
Figure 3
Figure 3
Structure of full-length RAGE. RAGE consists of three extracellular domains (V, C1, and C2), a transmembrane region and an intracellular cytoplasmic tail. The V-domain contains 23–116 amino acid residues and functions as ligand binding site. The C1 and C2 domains contain 124–221 and 227–317 amino acid residues, respectively. The transmembrane spinning helix consists of 343–363 amino acid residues. The short cytoplasmic tail containing 364–404 amino acid residues functions as signal transduction initiator.
Figure 4
Figure 4
Different pathological consequences of altered AGE–RAGE axis in the neurodegeneration.
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