Astrocyte activation by fibroblast growth factor‐1 and motor neuron apoptosis: implications for amyotrophic lateral sclerosis

Abstract

Fibroblast growth factor-1 (FGF1 or acidic FGF) is highly expressed in motor neurons. FGF-1 is released from cells by oxidative stress, which might occur from SOD-1 aberrant function in amyotrophic lateral sclerosis (ALS). Although FGF-1 is known to be neuroprotective after spinal cord injury or axotomy, we found that FGF-1 could activate spinal cord astrocytes in a manner that decreased motor neuron survival in co-cultures. FGF-1 induced accumulation of the FGF receptor 1 (FGFR1) in astrocyte nuclei and potently stimulated nerve growth factor (NGF) expression and secretion. The FGFR1 tyrosine kinase inhibitor PD166866 prevented these effects. Previously, we have shown that NGF secretion by reactive astrocytes induces motor neuron apoptosis through a p75 NTR -dependent mechanism. Embryonic motor neurons co-cultured on the top of astrocytes exhibiting activated FGFR1 underwent apoptosis, which was prevented by PD166866 or by adding either anti-NGF or anti-p75 NTR neutralizing antibodies. In the degenerating spinal cord of mice carrying the ALS mutation G93A of Cu, Zn superoxide dismutase, FGF-1 was no longer localized only in the cytosol of motor neurons, while FGFR1 accumulated in the nuclei of reactive astrocytes. These results suggest that FGF-1 released by oxidative stress from motor neurons might have a role in activating astrocytes, which could in turn initiate motor neuron apoptosis in ALS through a p75 NTR -dependent mechanism.

Astrocyte and Muscle-Derived Secreted Factors Differentially Regulate Motoneuron Survival

“…p75 NTR , a promiscuous receptor for multiple neurotrophins, is implicated in both the survival and death of MNs and is highly expressed in this population during development and in response to injury (McKay et al, 1996;Ferri et al, 1998;Wiese et al, 1999;Boyd and Gordon, 2001;Turner et al, 2003;Pehar et al, 2004;Cassina et al, 2005). Moreover, we verified p75 NTR expression in MNs after treatment with ACM and MCM (data not shown).…”

FGF-1 induces ATP release from spinal astrocytes in culture and opens pannexin and connexin hemichannels

“…Astrocytes from spinal cords of 1-d-old rat pups were prepared and cultured as described with minor modifications (21). Cultures were used after 15-20 d. Lucifer Yellow and Ethidium Permeability Assay.…”

“…However, in vivo extracellular ATP released from astrocytes could induce release of more ATP from microglia, at least in part through HCs (4), and enhance the inflammatory response acting as a paracrine signal to a different type of cell. Activated microglia also release other proinflammatory molecules including TNF-α and IL-1β that could act on astrocytes in concert with FGF-1 (which may be released by dying neurons) (21). Astrocyte Px1 and Cx HCs could release bioactive molecules and reduce net uptake of extracellular K + and glutamate, leading to excitotoxicity (44); also, decreased coupling would hinder spatial buffering by astrocytes.…”

“…FGF-1 activates spinal astrocytes, and activated astrocytes are implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis (21,22). To explore inflammatory mechanisms in spinal cord, we used rat and mouse spinal astrocytes in culture.…”

“…S2) and the morphological changes induced by FGF-1 (as also shown by ref. 21, using the related compound, PD166866).…”