The role of AMPA receptors and VEGF in ALS.

Abstract

The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is a complex and multifactorial process. Both excitotoxicity (excessive stimulation of glutamate receptors) and a shortage of the vascular endothelial growth factor (VEGF) have been implicated in the disease pathogenesis. In this study, both disease mechanisms were further characterized and their therapeutic potential was evaluated. Motor neurons were found to be particularly vulnerable to AMPA receptor stimulation (one subtype of glutamate receptors) and the toxicity was initiated by the influx of calcium ions through the AMPA receptors. Only AMPA receptors that lack a certain subunit (GluR2) are permeable to calcium ions, and compared to other neurons motor neurons had low GluR2 levels. Reducing GluR2 levels aggravated motor neuron death in culture and accelerated the process of motor neuron degeneration in vivo. The regulation of GluR2 expression was investigated further. Astrocytes were found to influence neuronal GluR2 expression and thus their vulnerability to excitotoxicity. In addition, the growth factor VEGF, which could slow down motor neuron degeneration in rats, stimulated GluR2 expression in motor neurons and protected against excessive AMPA receptor stimulation, providing a link between two important disease mechanisms in ALS. Clinical trials with AMPA receptor antagonists and VEGF will hopefully lead to a better treatment of patients with ALS.