Glutamate neurotransmission and metabolism are finely modulated by the retinal network, where the efficient processing of visual information is shaped by the differential distribution and composition of glutamate receptors and transporters. However, disturbances in glutamate homeostasis can result in glutamate excitotoxicity, a major initiating factor of common neurodegenerative diseases. Within the retina, glutamate excitotoxicity can impair visual transmission by initiating degeneration of neuronal populations, including retinal ganglion cells (RGCs). The vulnerability of RGCs is observed not just as a result of retinal diseases but has also been ascribed to other common neurodegenerative and peripheral diseases. In this review, we describe the vulnerability of RGCs to glutamate excitotoxicity and the contribution of different glutamate receptors and transporters to this. In particular, we focus on the N-methyl-d-aspartate (NMDA) receptor as the major effector of glutamate-induced mechanisms of neurodegeneration, including impairment of calcium homeostasis, changes in gene expression and signalling, and mitochondrial dysfunction, as well as the role of endoplasmic reticular stress. Due to recent developments in the search for modulators of NMDA receptor signalling, novel neuroprotective strategies may be on the horizon.

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The brain is one of the most energy-requiring organs in the human body. Mitochondria not only generate this energy, but are centrally involved critical cellular functions including maintenance of calcium homeostasis, synthesis of biomolecules, and cell signaling. Even though neurons and astrocytes preferentially use different energy substrates and metabolic pathways, these two cell types are intricately linked in their energy metabolism. Recently it has become clear that astrocytes have a key role in the regulation and support of the neuronal mitochondrial quality control, yet several questions remain unanswered to fully understand the mechanisms of mitochondrial function, transport, turnover and degradation in astrocytes. Alzheimer's disease is the most common neurodegenerative disorder, the exact mechanisms of which remain incompletely understood. The fact that astrocytic mitochondrial dysfunction is an early event in the pathogenesis of Alzheimer's disease suggests that more research on mitochondrial function and impairment is required in the hopes of disease alleviation in the future.

Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization and degradation of neuronal mitochondria are significantly increased in astrocytes isolated from aged AD mouse brains. We also demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and aged AD astrocytes. Significant increases in the mitophagy regulator Ambra1 were observed in the aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of aged AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.