Astrocyte-Neuron Interaction via the Glutamate-Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration

Abstract

Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood-brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate-glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders.

Keywords: astrocyte–neuron integrity; glutamate transporters; glutamate–glutamine cycle; glutamine transporters; tau-dependent neurodegeneration.

Figure 1

Schematic representation of the Gln and Glu transport and metabolism in astrocytes and neurons. Glu released from synaptic terminals is taken up by surrounding astrocytes via Glu transporters and converted to Gln in GS-mediated reaction. A proportion of Gln is released into the extracellular space by Gln carriers, with a predominant role in the N system. In addition to N system, the release of Gln from astrocytes is mediated by transporters belonging to systems L and ASC. Extracellular Gln is taken up into GABAergic and glutamatergic neurons by the unidirectional system A transporters. Once in neurons, Gln serves as a substrate for the mitochondrial enzyme PAG for the synthesis of Glu that can supply the neurotransmission pool of Glu or can be converted to GABA by GAD or to αKG by GDH.

Figure 2

Schematic representation of the disturbed astrocyte–neuron network in tau-dependent neurodegeneration based on the previously described results [81]. Astroglia after exposure to the mutant tau-expressing neurons, acquire functional deficit resulting in loss of neurosupportive properties and/or gain of neurotoxic function. One of the pathological events is associated with overexpression of GFAP and S100β protein as a consequence of the astrocytic phenotype reactivity. Moreover, astrocytes became deprived of key molecules that support glutamate (GLAST, GLT-1) and glutamine homeostasis (System N, System A carries) and synaptogenesis relevant processes (TSP-1, PSD95, SNP). Up arrows indicate targets that are increased; down arrows represent declined targets; lightning arrows mean deregulation of the glutamine transporting systems function in the astrocytic and neuronal tau-mediated neurodegeneration. For more details, see Section 5 and Section 6.