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

• Published in: Neuropharmacology 2021-06, Vol.190, p.108541-108541, Article 108541
• Main Authors: Bensalem, Julien, Fourrier, Célia, Hein, Leanne K., Hassiotis, Sofia, Proud, Christopher G., Sargeant, Timothy J.
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy - drug effects; AZD2014; Benzamides - pharmacology; Brain; Cerebral Cortex - drug effects; Green Fluorescent Proteins - genetics; HeLa Cells; Humans; Liver - drug effects; Lysosome; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic target of rapamycin kinase; Mice; Mice, Transgenic; Microtubule-Associated Proteins - drug effects; Microtubule-Associated Proteins - metabolism; Morpholines - pharmacology; mTOR; MTOR Inhibitors - pharmacology; Pyrimidines - pharmacology; TF-LC3; Vistusertib
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2021.108541

Autophagy is a catabolic process that collects and degrades damaged or unwanted cellular materials such as protein aggregates. Defective brain autophagy has been linked to diseases such as Alzheimer's disease. Autophagy is regulated by the protein kinase mTOR (mechanistic target of rapamycin). Although already demonstrated in vitro, it remains contentious whether inhibiting mTOR can enhance autophagy in the brain. To address this, mice were intraperitoneally injected with the mTOR inhibitor AZD2014 for seven days. mTOR complex 1 (mTORC1) activity was decreased in liver and brain. Autophagic activity was increased by AZD2014 in both organs, as measured by immunoblotting for LC3 (microtubule-associated proteins-1A/1B light chain 3B) and measurement of autophagic flux in the cerebral cortex of transgenic mice expressing the EGFP-mRFP-LC3B transgene. mTOR activity was shown to correlate with changes in LC3. Thus, we show it is possible to promote autophagy in the brain using AZD2014, which will be valuable in tackling conditions associated with defective autophagy, especially neurodegeneration. [Display omitted] •Injection of AZD2014 for 7 days inhibits mTORC1 activity in mouse liver and brain.•AZD2014 increases autophagy in liver and brain.•Inhibition of mTORC1 activity by AZD2014 correlates with autophagy alteration.