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Inhibiting mTOR activity using AZD2014 increases autophagy in the mouse cerebral cortex

Julien Bensalem1, Célia Fourrier1, Leanne K Hein1

  • 1Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, Australia.

Neuropharmacology
|April 1, 2021
PubMed

Insights

Inhibiting the mechanistic target of rapamycin (mTOR) with AZD2014 successfully enhanced autophagy in the brain. This finding offers a potential therapeutic strategy for neurodegenerative diseases linked to impaired autophagy.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Pharmacology

Background:

  • Autophagy, a cellular degradation process, is crucial for maintaining cellular health.
  • Defective autophagy in the brain is implicated in neurodegenerative diseases like Alzheimer's disease.
  • The protein kinase mTOR (mechanistic target of rapamycin) regulates autophagy, but its inhibition's effect on brain autophagy remains debated.

Purpose of the Study:

  • To investigate whether inhibiting mTOR can enhance autophagy in the brain.
  • To assess the efficacy of the mTOR inhibitor AZD2014 in promoting brain autophagy in vivo.

Main Methods:

  • Mice were treated with the mTOR inhibitor AZD2014 via intraperitoneal injection for seven days.
  • mTOR complex 1 (mTORC1) activity was measured in liver and brain tissues.
  • Autophagic activity was assessed using immunoblotting for LC3 (microtubule-associated proteins-1A/1B light chain 3B) and autophagic flux measurements in transgenic mice.

Main Results:

  • AZD2014 treatment decreased mTORC1 activity in both the liver and brain.
  • Autophagic activity significantly increased in both organs following AZD2014 administration.
  • Changes in LC3 levels correlated with altered mTOR activity, supporting the drug's mechanism.

Conclusions:

  • Inhibition of mTOR with AZD2014 effectively promotes autophagy in the brain.
  • This study demonstrates a viable strategy for enhancing brain autophagy.
  • Targeting mTOR could be a valuable therapeutic approach for neurodegenerative conditions characterized by defective autophagy.
Keywords:
AZD2014AutophagyBrainHeLa cellsLysosomeMechanistic target of rapamycin kinaseTF-LC3VistusertibmTOR

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