Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder of unknown pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Oxidative stress, microglial activation and inflammatory responses seem to contribute to the pathogenesis. The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules. The formation of advanced glycation end products (AGEs), the first ligand of RAGE identified, requires a complex series of reactions including nonenzymatic glycation and free radical reactions involving superoxide-radicals and hydrogen peroxide. Binding of RAGE ligands results in activation of nuclear factor-kappaB (NF-κB). We show that RAGE ablation protected nigral dopaminergic neurons against cell death induced by the neurotoxin MPTP that mimics most features of PD. In RAGE-deficient mice the translocation of the NF-κB subunit p65 to the nucleus, in dopaminergic neurons and glial cells was inhibited suggesting that RAGE involves the activation of NF-κB. The mRNA level of S100, one of the ligands of RAGE, was increased after MPTP treatment. The dopaminergic neurons treated with MPP+ and S100 protein showed increased levels of apoptotic cell death, which was attenuated in RAGE-deficient mice. Our results suggest that activation of RAGE contributes to MPTP/MPP+-induced death of dopaminergic neurons that may be mediated by NF-κB activation.

Aβ induces PUMA activation: a new mechanism for Aβ-mediated neuronal apoptosis

“…However, aberrant apoptosis has been involved in several neurodegenerative conditions including Parkinson's disease, Huntington disease, and AD (Ghavami et al, 2014;Meng et al, 2013;Teismann et al, 2012). Our study also confirm that apoptosis occurs in SH-SY5Y cells and primary neurons exposed to Ab.…”

Receptor for advanced glycation end-products in neurodegenerative diseases

“…Indeed, recent in vitro studies have even shown that AGEs induce the aggregation of α-syn in vitro (Lee et al, 2009;Padmaraju et al, 2011). The pathogenesis of the disease remains largely unclear; however, a few potential molecular contributors such as RAGE have been proposed (Teismann et al, 2012;Gao et al, 2014). RAGE has been found in neuronal Lewy bodies, whose presence is indicative of oxidative stress and neuroinflammation (Dalfo et al, 2005).…”

The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

“…First, the same AGER rs2070600 SNP that was implicated in CA1 atrophy during AD, was also correlated to the highest risk for PD development of all known AGER SNPs in a Turkish cohort GWAS (N=174 PD patients and N=150 healthy controls) [89]. In addition, when compared to healthy controls, PD patients have recently been shown to possess higher concentrations of RAGE ligands S100B and HMGB1 in the substantia nigra and cerebral spinal fluid (CSF) [90][91][92]. In rodent models, numerous studies have indicated that animals derive prominent protection from PD-like impairments when RAGE signaling was blocked through genetic ablation of S100b/Ager or by the administration of a RAGE inhibitor, FPS-ZM1, a BBB permeable, high affinity, multimodal blocker of RAGE [90].…”