Neurotoxicity of ischemic astrocytes involves STAT3‐mediated metabolic switching and depends on glycogen usage

• Published in: Glia 2023-06, Vol.71 (6), p.1553-1569
• Main Authors: Borbor, Mina, Yin, Dongpei, Brockmeier, Ulf, Wang, Chen, Doeckel, Marius, Pillath‐Eilers, Matthias, Kaltwasser, Britta, Hermann, Dirk M., Dzyubenko, Egor
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Astrocytes - metabolism; astrocyte‐neuronal interaction; cerebral ischemia; Cyclic S-Oxides - metabolism; Cyclic S-Oxides - pharmacology; Degeneration; Gliosis; Glutamatergic transmission; Glycogen; Glycogens; Glycolysis; Hypoxia; Inflammation; Ischemia; Ischemia - metabolism; Lactic acid; metabolic reprogramming; Metabolism; Mice; Mitochondria; Neural networks; Neurodegeneration; Neurons; Neuroprotection; Neurotoxicity; Nuclear transport; oxidative phosphorylation; Preconditioning; Pyruvate kinase; Pyruvic acid; Reperfusion; Signaling; Stat3 protein; STAT3 Transcription Factor - metabolism; Stroke; Stroke - metabolism; Switching; Synapses; synaptic degeneration; Translocation
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24357

Astrocytic responses are critical for the maintenance of neuronal networks in health and disease. In stroke, reactive astrocytes undergo functional changes potentially contributing to secondary neurodegeneration, but the mechanisms of astrocyte‐mediated neurotoxicity remain elusive. Here, we investigated metabolic reprogramming in astrocytes following ischemia–reperfusion in vitro, explored their role in synaptic degeneration, and verified the key findings in a mouse model of stroke. Using indirect cocultures of primary mouse astrocytes and neurons, we demonstrate that transcription factor STAT3 controls metabolic switching in ischemic astrocytes promoting lactate‐directed glycolysis and hindering mitochondrial function. Upregulation of astrocytic STAT3 signaling associated with nuclear translocation of pyruvate kinase isoform M2 and hypoxia response element activation. Reprogrammed thereby, the ischemic astrocytes induced mitochondrial respiration failure in neurons and triggered glutamatergic synapse loss, which was prevented by inhibiting astrocytic STAT3 signaling with Stattic. The rescuing effect of Stattic relied on the ability of astrocytes to utilize glycogen bodies as an alternative metabolic source supporting mitochondrial function. After focal cerebral ischemia in mice, astrocytic STAT3 activation was associated with secondary synaptic degeneration in the perilesional cortex. Inflammatory preconditioning with LPS increased astrocytic glycogen content, reduced synaptic degeneration, and promoted neuroprotection post stroke. Our data indicate the central role of STAT3 signaling and glycogen usage in reactive astrogliosis and suggest novel targets for restorative stroke therapy. Main Points STAT3 mediates metabolic switching in ischemic astrocytes. Astrocytic STAT3 activation induces synaptic degeneration. Astrocytic glycogen phosphorylase supports synaptogenesis. Enrichment of astrocytic glycogen reduces neurodegeneration post stroke.