Journal
METABOLIC BRAIN DISEASE
Volume 36, Issue 7, Pages 2079-2088Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11011-021-00787-4
Keywords
Cognitive dysfunction; Insulin-like growth factor I; Obesity; Pyroptosis; Tau proteins
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Funding
- TIANJIN UNIVERSITY (China)
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The study suggests that IGF-1 treats obesity-induced cognitive dysfunction by improving tau pathology and neuronal pyroptosis, with activation of the Nrf2/HO-1 signaling pathway being a key mechanism.
Insulin-like growth factor-1 (IGF-1) improves obesity-induced cognitive dysfunction, but its mechanism is not fully clarified. The aim of the study was to reveal whether IGF-1 treated cognitive dysfunction by improving tau pathology and neuronal pyroptosis in high-fat diet mice. During in vitro experiment, C57BL/6J mice were fed with high-fat diet, and were treated with PEG-IGF-1, IGF-1 receptor blocker AXL1717, HO-1 blocker Znpp IX or their combinations. Cognitive function was evaluated using Morris water maze. Expression of Nrf2, HO-1, p-tau, NLRP3, caspase-1 and IL-1 beta in hippocampus was determined using western blotting. Pyroptosis rate in hippocampus was measured using flow cytometry. During in vivo experiment, HN-h cells were treated with palmitic acid, pyroptosis blocker nonecrosulfonamide or their combinations. The expression of the proteins and rate of pyroptosis were also measured using western blotting and flow cytometry. During in vitro experiment, high-fat diet mice showed cognitive dysfunction, significant hyperphosphorylation of tau protein and neuronal pyroptosis in hippocampus compared with the sham mice. After exogenous IGF-1 treatment, these abnormalities were reversed and Nrf2/HO-1 signaling pathway was activated. Inhibition of the signaling pathway using AXL1717 or Znpp IX re-deteriorated cognitive function, tau pathology and neuronal pyroptosis in hippocampus. During in vivo experiment, inhibition of pyroptosis using nonecrosulfonamide improved tau pathology in palmitic acid-treated HN-h cells. Exogenous IGF-1 improved tau pathology induced by high-fat diet through inhibition of neuronal pyroptosis and activation of Nrf2/HO-1 signaling pathway.
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