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

Abstract

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 (p75 NTR ) 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 p75 NTR 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 p75 NTR +/+ mouse embryos but had no effect in p75 NTR -/-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 p75 NTR 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.

Pro-NGF secreted by astrocytes promotes motor neuron cell death

“…In contrast to the release of neurotrophic factors for neuronal survival, astrocytes can be detrimental in an activated state or during injury (Heales et al 2004;Pehar et al 2004). One potential trophic factor, NGF, had been proposed to induce motor neuron degeneration (Pehar et al 2004). In this study, we demonstrate that the precursor form of NGF, and not the mature form, can induce the death of embryonic spinal motor neurons.…”

“…Astrocytes play a crucial role in maintaining central nervous system (CNS) physiology during development and in adulthood (Heales et al 2004;Benarroch 2005). In contrast to the release of neurotrophic factors for neuronal survival, astrocytes can be detrimental in an activated state or during injury (Heales et al 2004;Pehar et al 2004). One potential trophic factor, NGF, had been proposed to induce motor neuron degeneration (Pehar et al 2004).…”

Sclérose latérale amyotrophique, jonction neuromusculaire et déficit énergétique

“…Parmi les candidats, se trouvent les cellules gliales (astrocytes, microglie, cellules de Schwann) ou les cellules musculaires [16]. Ainsi, le laboratoire de Luis Barbeito a montré que les astrocytes porteurs d'une SOD1m sont capables de provoquer l'apoptose de motoneurones sauvages via un méca-nisme impliquant le stress oxydant et le NGF (nerve growth factor) [17,18]. Ces travaux ont récemment été confirmés par d'autres [19,20] et suggèrent que l'astrocyte pourrait participer à la toxicité envers le motoneurone.…”

ALS: astrocytes take center stage, but must they share the spotlight?

“…While Nagai et al 1 found that neutralizing antibodies against NGF were not protective, culture conditions including the presence of glialderived neurotrophic factor, could have prevented NGF toxicity in the experimental system by activating survival pathways. 28 Thus, we cannot exclude NGF as a potential culprit in astrocyte toxicity.…”

“…A previous study indicated that astrocytic production of NGF when NO was present caused motor neuron death. 28 This may be applicable to the situation of motor neuron injury in ALS. While Nagai et al 1 found that neutralizing antibodies against NGF were not protective, culture conditions including the presence of glialderived neurotrophic factor, could have prevented NGF toxicity in the experimental system by activating survival pathways.…”