Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice

Abstract

The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5–10% of cases are familial, and of those, 15–20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.

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

“…Importantly, sRAGE treatment not only reduced motor neuron death but also decreased astrogliosis, indicating a more homeostatic profile in multiple cell types [99]. Altogether, a burgeoning body of literature suggests that RAGE activation, driven by an increased availability of ligands, is likely a contributing factor to ALS pathology.…”

“…Furthermore, this increase of RAGE and its ligands was recapitulated in one of the most commonly employed ALS rodent models, murine lines containing the familial G93A mutation in superoxide dismutase 1 (SOD1), as discovered in human ALS populations [3,99,100]. In these models, nerve growth factor (NGF) is post-translationally modified by oxidation and contributes to RAGE signaling-induced motor neuron death when normal motor neurons are co-cultured with SOD1 G93A astrocytes [101].…”

“…In the SOD1 G93A mice, daily administration of recombinant sRAGE extended lifespan and duration of healthy body weight, while slowing the onset of motor function loss [99]. Importantly, sRAGE treatment not only reduced motor neuron death but also decreased astrogliosis, indicating a more homeostatic profile in multiple cell types [99].…”

Glycation & the RAGE axis: targeting signal transduction through DIAPH1

“…In a recent study, Juranek and colleagues showed that administration of the soluble form of RAGE, sRAGE, to SOD1 G93A mice significantly prolonged life span and delayed disease progression compared to vehicle treatment [32]. At the end stage of disease, spinal cord tissue revealed higher numbers of neurons and less astrogliosis in the sRAGE-treated group vs. the mice receiving vehicle.…”

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1G93Amouse model of amyotrophic lateral sclerosis

“…Multiple studies have demonstrated that RAGE and its inflammatory ligands AGE, S100β and HMGB1 are up-regulated in the spinal cord of human ALS patients compared to healthy controls [6,11]. Prior studies have also demonstrated that inhibition of RAGE using soluble RAGE form has beneficial effects on survival and disease progression in animal models of ALS [10,12], suggesting RAGE could play a pathogenic role in the disease. Although these studies have indicated detrimental actions of RAGE activation in ALS pathogenesis, the specific molecular mechanism by which RAGE contributes to neurodegeneration remains unknown.…”