The role of astroglia in neuroprotection

Abstract

Astrocytes are the main neural cell type responsible for the maintenance of brain homeostasis. They form highly organized anatomical domains that are interconnected into extensive networks. These features, along with the expression of a wide array of receptors, transporters, and ion channels, ideally position them to sense and dynamically modulate neuronal activity. Astrocytes cooperate with neurons on several levels, including neurotransmitter trafficking and recycling, ion homeostasis, energy metabolism, and defense against oxidative stress. The critical dependence of neurons upon their constant support confers astrocytes with intrinsic neuroprotective properties which are discussed here. Conversely, pathogenic stimuli may disturb astrocytic function, thus compromising neuronal functionality and viability. Using neuroinflammation, Alzheimer's disease, and hepatic encephalopathy as examples, we discuss how astrocytic defense mechanisms may be overwhelmed in pathological conditions, contributing to disease progression.

Figure 1.. Human astrocytes are more complex then their rodent counterparts. Typical human (A) and mouse (B) protoplasmic astrocytes are shown at the same scale for comparison. Based on glial fibrillary acidic protein (GFAP) immunostaining, human protoplasmic astrocytes are 2.5-fold larger and project 10 times more main processes than mouse astrocytes. (GFAP, white. Scale bar, 20 µM). Adapted from ref 2: Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29:3276-3287. Copyright © Society for Neuroscience 2009

Figure 2.. Simplified representation of the main roles of astrocytes in brain homeostasis. Pink box: glutamate-glutamine cycle. Astrocytic excitatory amino acid transporters (EAATs) are responsible for the uptake of a large fraction of glutamate at the synapse. Glutamate is converted into glutamine by glutamine synthetase (GS) and shuttled back to neurons for glutamate resynthesis. Blue boxes: Lactate shuttle. Glutamate uptake by astrocytes is accompanied by Na⁺ entry which is counteracted by the action of the Na⁺/K⁺ ATPase. The resulting increase in ADP/ATP ratio triggers anaerobic glucose utilization in astrocytes and glucose uptake from the circulation through the glucose transporter GLUT1 . The lactate produced is shuttled to neurons through monocarboxylate transporters (mainly MCT-1 in astrocytes and MCT-2 in neurons), where it can be used as an energy substrate after its conversion to pyruvate. Yellow box: pH buffering. Abundant carbonic anhydrase (CA) in astrocytes converts CO² into H⁺ and HCO₃ ^-. Two HCO₃ ^- are transported into the extracellular space along vyith one Na'via the Na⁺-HCO₃ ^- cotransporter (NBC), thereby increasing the extracellular buffering power. Protons left in the glial compartment may drive the transport of lactate outside of astrocytes and into neurons through MCTs. Excess H⁺ in neurons is extruded via sodium-hydrogen exchange (NHE). Orange box: K⁺ buffering. Astrocytes buffer excess K⁺ released into the extracellular space as a result of neuronal activity. Potassium ions travel through the astrocytic syncitium down their concentration gradient and are released in sites of lover concentration. Green box: Glutathione metabolism. Astrocytes release glutathione (GSH) in the extracellular space where it is cleaved by the astrocytic ectoenzyme γ-glutamyl transpeptidase (γGT). The resulting CysGly selves as a precursor for neuronal GSH synthesis. X represents an acceptor for the γ-glutamyl moiety in the reaction catalyzed by γGT.

Figure 3.. Astrocytic endfeet in humans. (A) Protoplasmic astrocytes project specialized processes tov/ards the intraparenchymal vasculature (part of a blood vessel is highlighted in the yellow box) (glial fibrillary acidic protein - (GFAP), white; nuclei (4',6diamidino-2-phenylindole - DAPI), blue. Scale bar, 20 µM). (B) Astrocytic endfeet are in close contact with blood vessels and almost entirely cover their surface (GFAP, white. Scale bar, 20 µM). Adapted from ref 2: Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes, J Neurosci. 2009;29:3276-3287. Copyright © Society for Neuroscience 2009