LIF, a Novel Myokine, Protects Against Amyloid-Beta-Induced Neurotoxicity via Akt-Mediated Autophagy Signaling in Hippocampal Cells

Hye Jeong Lee, Jung Ok Lee, Yong Woo Lee, Shin Ae Kim, Il Hyeok Seo, Jeong Ah Han, Min Ju Kang, Su Jin Kim, Yun Ho Cho, Joong Jean Park, Jongil Choi, Sun-Hwa Park, Hyeon Soo Kim

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Abstract

BACKGROUND: Leukemia inhibitory factor, a novel myokine, is known to be associated with neural function, but the underlying molecular mechanism remains unclear. METHODS: HT-22 mouse hippocampal cells, primary hippocampal cells, and Drosophila Alzheimer's disease model were used to determine the effect of leukemia inhibitory factor on neurons. Immunoblot analysis and immunofluorescence method were used to analyze biological mechanism. RESULTS: Leukemia inhibitory factor increased Akt phosphorylation in a phosphoinositide-3-kinase-dependent manner in hippocampal cells. Leukemia inhibitory factor also increased the phosphorylation of the mammalian target of rapamycin and the downstream S6K. Leukemia inhibitory factor stimulated the phosphorylation of signal transducer and activator of transcription via extracellular signal-regulated kinases. Leukemia inhibitory factor increased c-fos expression through both Akt and extracellular signal-regulated kinases. Leukemia inhibitory factor blocked amyloid β-induced neural viability suppression and inhibited amyloid β-induced glucose uptake impairment through the block of amyloid β-mediated insulin receptor downregulation. Leukemia inhibitory factor blocked amyloid β-mediated induction of the autophagy marker, microtubule-associated protein 1A/1B-light chain 3. Additionally, in primary prepared hippocampal cells, leukemia inhibitory factor stimulated Akt and extracellular signal-regulated kinase, demonstrating that leukemia inhibitory factor has physiological relevance in vivo. Suppression of the autophagy marker, light chain 3II, by leukemia inhibitory factor was observed in a Drosophila model of Alzheimer's disease. CONCLUSIONS: These results demonstrate that leukemia inhibitory factor protects against amyloid β-induced neurotoxicity via Akt/extracellular signal-regulated kinase-mediated c-fos induction, and thus suggest that leukemia inhibitory factor is a potential drug for Alzheimer's disease.

Original languageEnglish
Pages (from-to)402-414
Number of pages13
JournalThe international journal of neuropsychopharmacology
Volume22
Issue number6
DOIs
Publication statusPublished - 2019 Jun 3

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Keywords

  • Akt
  • Alzheimer’s disease
  • autophagy
  • LIF
  • mTOR
  • myokine

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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