Adaptive regulation of the brain's antioxidant defences by neurons and astrocytes

Abstract

The human brain generally remains structurally and functionally sound for many decades, despite the post-mitotic and non-regenerative nature of neurons. This is testament to the brain's profound capacity for homeostasis: both neurons and glia have in-built mechanisms that enable them to mount adaptive or protective responses to potentially challenging situations, ensuring that cellular viability and functionality is maintained. The high and variable metabolic and mitochondrial activity of neurons places several demands on the brain, including the task of neutralizing the associated reactive oxygen species (ROS) produced, to limit the accumulation of oxidative damage. Astrocytes play a key role in providing antioxidant support to nearby neurons, and redox regulation of the astrocytic Nrf2 pathway represents a powerful homeostatic regulator of the large cohort of Nrf2-regulated antioxidant genes that they express. In contrast, the Nrf2 pathway is weak in neurons, robbing them of this particular homeostatic device. However, many neuronal antioxidant genes are controlled by synaptic activity, enabling activity-dependent increases in ROS production to be offset by enhanced antioxidant capacity of both glutathione and thioredoxin-peroxiredoxin systems. These distinct homeostatic mechanisms in neurons and astrocytes together combine to promote neuronal resistance to oxidative insults. Future investigations into signaling between distinct cell types within the neuro-glial unit are likely to uncover further mechanisms underlying redox homeostasis in the brain.

Fig. 1

Astrocytes and neuronal activity play distinct, cooperative roles in neuronal redox homeostasis. Astrocytes respond to mild oxidative stress and other inducers of the Nrf2 pathway by turning on a program of Nrf2-mediated antioxidant gene expression, with consequent synthesis of GSH. GSH is exported via Mrp1 and degraded (by Ggt1), with one or more degradation products taken up by neurons and fed into their own GSH biosynthesis pathway. Thus, while astrocytes provided support in providing the building blocks for GSH production, neurons still require the capacity to make use of these raw materials. This capacity is controlled by synaptic activity-induced signaling pathways, via the transcriptional control of a number of key genes involved in GSH synthesis, peroxidation and recycling.