Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

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.

Keywords: Alzheimer’s disease; Parkinson’s disease; astrocytes; metabolism; neurodegeneration; neurons.

Figure 1

The overview of astrocytic functions. Astrocytes support neuronal functions by providing energy substrates and supporting antioxidant defense. Their ability to participate in the immune response by sensing cytokines secreted by microglia, as well as participation in neurovascular coupling positions them as a crucial component of the interplay between various brain cell types. Figure created with BioRender.com using images adapted from Servier Medical Art by Servier, licensed under a Creative Common Attribution 3.0 Unported License http://smart.servier.com/.

Figure 2

Disrupted Astrocyte-Neuron metabolic interplay in PD and AD. Metabolic interaction between astrocytes and neurons is disrupted in AD and PD. Both diseases present cerebral hypoperfusion with associated degradation of BBB integrity which might impact the function of the glymphatic system. Neurovascular coupling is impaired in AD. Cerebral hypoperfusion is accompanied by reduced glucose metabolism which will transversely affect downstream pathways such as the ANLS. Astrocytic glycogen metabolism is regulated by noradrenaline and insulin being impaired in both diseases. Neuronal PPP is upregulated in AD and late PD as a response to increased oxidative stress. Oxidative stress is further exacerbated by disruption of the GSH flux from astrocytes to neurons. The transfer of neuronal peroxidated FA to astrocytes where they are degraded through FAO is impaired by the AD-related ApoE4 isoform, leading to the accumulation of such toxic FA. The Glu/GLn cycle is impaired in both conditions, due to defective removal of glutamate from the synaptic cleft which leads to excitotoxicity-induced neuronal loss. (Gluc, glucose; Glu, glutamate; Gln, glutamine; Lac, lactate; Pyr, pyruvate; Glyc, glycogen; R5P, ribose 5-phosphate; G6P, glucose 6-phosphate; GSH, glutathione; Cys,cysteine; Gly, glycine; FAO, fatty acid oxidation; TCA, tricarboxylic acid cycle). Figure created with images adapted from Servier Medical Art by Servier; licensed under a Creative Common Attribution 3.0 Unported License http://smart.servier.com/.

Figure 3

Astrocytic uptake of protein aggregates. Astrocytes can internalize both Aβ and α-synuclein which might originate either from other astrocytes or neurons. Uptaken aggregates were shown to affect mitochondrial function, in particular their respiration capacity and coupling status. Figure created with BioRender.com using images adapted from Servier Medical Art by Servier, licensed under a Creative Common Attribution 3.0 Unported License http://smart.servier.com/.