Astrocytes are critical for neuronal function and survival. Astrocytes ensure metabolic support for neurons, in particular by providing lactate derived from aerobic glycolysis on-demand through a mechanism known as the Astrocyte-Neuron Lactate Shuttle (ANLS). Previous results from our laboratory showed that exposure of astrocytes to pro- and anti-inflammatory cytokines combined with the pathogenic form of amyloid beta 25–35 (Gavillet et al., 2008; Allaman et al., J. Neurosci., 2010; and Bélanger et al., 2011) induced marked changes in their metabolic phenotype. However, In the present study, we exposed cortical astrocyte cultures to different amyloid beta 1-42 aggregates alone or in combination with pro-inflammatory cytokines, including complement component C1q, TNF-alpha, and IL1-alpha. Global analysis of the datasets highlighted several metabolic pathways that are enriched in AD biomarkers in the CSF of patients. Several metabolic pathways were affected by the treatments, such as increased glycolytic flux at the expense of mitochondrial oxidation associated with an increase in glutaminolysis. A global change in amino acid metabolism was apparent. For instance, markers of glutathione, creatine, and nitric oxide synthase activation were observed. These pathways have been reported to have a neuroprotective effect. Furthermore, taurine and hypotaurine, in addition to their precursors, were increased in the secretome upon treatment with amyloid aggregates and pro-inflammatory cytokines. Interestingly, the levels of vitamin B6 (pyridoxine) significantly decreased under the treatment conditions. In addition, pyridoxamine, in its active form as pyridoxamine phosphate, significantly decreased in the cell pellet. Finally, low levels of vitamin B6 in patients with AD have been linked to increased homocysteine metabolism, and its related pathways, which was evident in our datasets.
| Date of Award | Jul 2023 |
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| Original language | English (US) |
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| Awarding Institution | - Biological, Environmental Sciences and Engineering
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| Supervisor | Pierre Magistretti (Supervisor) |
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