Abstract
Converging evidence made clear that declining brain energetics contribute to aging and are implicated in the initiation and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Indeed, both pathologies involve instances of hypometabolism of glucose and oxygen in the brain causing mitochondrial dysfunction, energetic failure and oxidative stress. Importantly, recent evidence suggests that astrocytes, which play a key role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. Therefore, exploring how the neuro-supportive role of astrocytes may be impaired in the context of these disorders has great therapeutic potential. In the following, we will discuss some of the so far identified features underlining the astrocyte-neuron metabolic crosstalk. Thereby, special focus will be given to the role of mitochondria. Furthermore, we will report on recent advancements concerning iPSC-derived models used to unravel the metabolic contribution of astrocytes to neuronal demise. Finally, we discuss how mitochondrial dysfunction in astrocytes could contribute to inflammatory signaling in neurodegenerative diseases.
Highlights
Neurodegenerative diseases can be grouped into a large class of disorders characterized by the gradual loss of various neuronal populations [1]
It should be noted that, to date, very few metabolic findings from mouse models have been validated in human astrocytes
Various protocols for the generation of pure astrocyte cultures from iPSCs have been published in the recent years
Summary
Neurodegenerative diseases can be grouped into a large class of disorders characterized by the gradual loss of various neuronal populations [1]. A recent mouse study showed that physiological ROS levels in astrocytes are needed to regulate metabolic rewiring, which modulates the PPP flux with potential implications on neuronal survival and cognitive impairment This mechanism engaged the function of nuclear factor E2-related factor 2 (NRF2) and contributed to prevent disproportionate ROS release outside of the cell [78]. We observed the development of numerous protocols for the generation of iPSC-derived astrocytes [106,107,108,109,110] [for an extensive review of earlier protocols see [111]], allowing researchers to shed light on the involvement of astroglia in the pathogenesis of human neurodegenerative diseases Such tools proved to be useful in studying metabolic alterations in the brain (Table 1), in particular taking into account the above-mentioned contribution of astrocytic metabolism to the maintenance of neuronal function. This spontaneous upregulation of mitochondrial clearance ensures astrocyte survival and may, in turn, influence neuronal metabolism [143]
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