Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder of largely unknown pathogenesis. Recent studies suggest that enhanced oxidative stress and neuroinflammation contribute to the progression of the disease. Mounting evidence implicates the receptor for advanced glycation end-products (RAGE) as a significant contributor to the pathogenesis of certain neurodegenerative diseases and chronic conditions. It is hypothesized that detrimental actions of RAGE are triggered upon binding to its ligands, such as AGEs (advanced glycation end products), S100/calgranulin family members, and High Mobility Group Box-1 (HMGB1) proteins. Here, we examined the expression of RAGE and its ligands in human ALS spinal cord. Tissue samples from age-matched human control and ALS spinal cords were tested for the expression of RAGE, carboxymethyllysine (CML) AGE, S100B, and HMGB1, and intensity of the immunofluorescent and immunoblotting signals was assessed. We found that the expression of both RAGE and its ligands was significantly increased in the spinal cords of ALS patients versus age-matched control subjects. Our study is the first report describing co-expression of both RAGE and its ligands in human ALS spinal cords. These findings suggest that further probing of RAGE as a mechanism of neurodegeneration in human ALS is rational.
Highlights
Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder of upper and lower motor neurons manifested by progressive muscle wasting, muscular atrophy, and subsequent respiratory complications, leading to paralysis of respiratory muscles and the diaphragm, with death usually occurring within 3–5 years after diagnosis (Rowland and Shneider, 2001)
We demonstrate by immunohistochemistry a significantly increased expression of receptor for advanced glycation end-products (RAGE) in human Amyotrophic lateral sclerosis (ALS) spinal cord versus control samples
We show in control tissue, sparse overlapping of RAGE-S100B, moderate RAGE-CML and RAGE-High Mobility Group Box-1 (HMGB1) immunostaining (Figures 4A,B and 5A,C) whereas in ALS tissue, we found a high degree of overlapping expression patterns for all ligands with RAGE (Figures 4A,B and 5B,D)
Summary
Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder of upper and lower motor neurons manifested by progressive muscle wasting, muscular atrophy, and subsequent respiratory complications, leading to paralysis of respiratory muscles and the diaphragm, with death usually occurring within 3–5 years after diagnosis (Rowland and Shneider, 2001). The. Increased Expression of RAGE and its Ligands in ALS pathogenesis of the disease is largely unknown; growing evidence suggests that the progressive neurodegeneration of motor neurons in ALS results from a combination of multiple contributing factors, such as oxidative stress, neuroinflammation, glutamate toxicity, mitochondrial dysfunction, neurofilament disorganization, impaired axonal transport, and excessive neuronal apoptosis (Mitchell and Borasio, 2007; Brites and Vaz, 2014). The RAGE belongs to the family of the cell surface immunoglobulins and plays an important role in inflammation, oxidative stress, and cellular dysfunction in a number of conditions and diseases (Schmidt et al, 2000; Bierhaus et al, 2004; Daffu et al, 2013). RAGE has gained attention as a potential contributor to the pathogenesis of various neurodegenerative diseases and conditions, such as Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, Creutzfeldt-Jakob disease, diabetic neuropathy, familial amyloid polyneuropathy, Charcot neuroarthropathy, and vasculitic neuropathy (Juranek et al, 2015)
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