Journal
JOURNAL OF NEUROINFLAMMATION
Volume 20, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12974-023-02722-z
Keywords
Alzheimer's disease; Glia; Lipid droplets; Mitochondria dynamics; DRP-1
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This study investigates the effect of amyloid-beta (A beta) on astrocyte mitochondria functionality and overall energy metabolism. The results demonstrate that A beta leads to abnormal fusion and excessive fission of astrocyte mitochondria, as well as mitochondrial swelling and increased phosphorylated DRP-1 levels. These changes result in altered energy metabolism.
BackgroundAstrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (A beta). However, in which way these A beta deposits influence their energy production remain unclear.MethodsThe aim of the present study was to investigate how A beta pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta(42) fibrils for 7 days and analyzed over time using different experimental approaches.ResultsOur results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the A beta-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the A beta-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid beta-oxidation and glycolysis.ConclusionsTaken together, our data conclude that A beta pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.
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