Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis

• Published in: Journal of neurochemistry 2004-04, Vol.89 (2), p.464-473
• Main Authors: Pehar, Mariana, Cassina, Patricia, Vargas, Marcelo R., Castellanos, Raquel, Viera, Liliana, Beckman, Joseph S., Estévez, Alvaro G., Barbeito, Luis
• Format: Article
• Language: English
• Subjects: amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Antibodies - pharmacology; Apoptosis - drug effects; astrocyte; Astrocytes - metabolism; Astrocytes - pathology; Astrocytes - secretion; Biological and medical sciences; Cell Extracts - pharmacology; Cells, Cultured; Culture Media, Conditioned - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Humans; Medical sciences; Mice; Mice, Transgenic; motor neuron; Motor Neurons - drug effects; Motor Neurons - metabolism; Motor Neurons - pathology; nerve growth factor; Nerve Growth Factor - antagonists & inhibitors; Nerve Growth Factor - biosynthesis; Nerve Growth Factor - secretion; Neurology; nitric oxide; Nitric Oxide - metabolism; p75 neurotrophin receptor; Peroxynitrous Acid - metabolism; Rats; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor - antagonists & inhibitors; Receptors, Nerve Growth Factor - biosynthesis; Spinal Cord - chemistry; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide Dismutase - genetics
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02357.x

Reactive astrocytes frequently surround degenerating motor neurons in patients and transgenic animal models of amyotrophic lateral sclerosis (ALS). We report here that reactive astrocytes in the ventral spinal cord of transgenic ALS‐mutant G93A superoxide dismutase (SOD) mice expressed nerve growth factor (NGF) in regions where degenerating motor neurons expressed p75 neurotrophin receptor (p75NTR) and were immunoreactive for nitrotyrosine. Cultured spinal cord astrocytes incubated with lipopolysaccharide (LPS) or peroxynitrite became reactive and accumulated NGF in the culture medium. Reactive astrocytes caused apoptosis of embryonic rat motor neurons plated on the top of the monolayer. Such motor neuron apoptosis could be prevented when either NGF or p75NTR was inhibited with blocking antibodies. In addition, nitric oxide synthase inhibitors were also protective. Exogenous NGF stimulated motor neuron apoptosis only in the presence of a low steady state concentration of nitric oxide. NGF induced apoptosis in motor neurons from p75NTR +/+ mouse embryos but had no effect in p75NTR –/– knockout embryos. Culture media from reactive astrocytes as well as spinal cord lysates from symptomatic G93A SOD mice‐stimulated motor neuron apoptosis, but only when incubated with exogenous nitric oxide. This effect was prevented by either NGF or p75NTR blocking‐antibodies suggesting that it might be mediated by NGF and/or its precursor forms. Our findings show that NGF secreted by reactive astrocytes induce the death of p75‐expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation. Thus, reactive astrocytes might contribute to the progressive motor neuron degeneration characterizing ALS.