IMR Press / FBL / Volume 25 / Issue 6 / DOI: 10.2741/4851

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Inhibition of p-mTOR represses transcription of PS1 and Notch 1-signaling
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1 Department of Pharmacology and Neuroscience, UNT Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107
2 Institute for Healthy Aging, UNT Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107
Front. Biosci. (Landmark Ed) 2020, 25(6), 1172–1183; https://doi.org/10.2741/4851
Published: 1 March 2020
Abstract

Presenilin-1 (PS1) protein is the catalytic subunit of the gamma-secretase, and participates in the processing of beta-amyloid precursor protein (APP) to produce Abeta peptide and Notch 1 receptor to release Notch intracellular domain (NICD) in the cytoplasm. NICD migrates to the nucleus and causes Notch signaling by increasing the expression of the Hes1 gene. The mammalian target of rapamycin (mTOR) controls cellular homeostasis, and its activity is inhibited by rapamycin. The buildup of Abeta increases the mTOR signaling, whereas decreasing mTOR signaling reduces Abeta levels suggesting an interrelationship between mTOR signaling and Abeta. Administration of rapamycin in 3XTg-AD mouse model of Alzheimer’s disease (AD) rescues cognitive deficits and ameliorates Abeta and Tau pathology. We have dissected the mechanisms by which rapamycin inhibits PS1 expression and Notch1 signaling. Our results demonstrated that rapamycin efficiently suppressed phosphorylation of mTOR (p-mTOR), and decreased expression of PS1-mRNA as well as p-p70S6K1, 4EBP1, PS1, NICD, and Hes1 protein levels. Therefore, rapamycin decreased PS1 protein levels and Notch 1 processing by inhibiting PS1 transcription.

Keywords
Alzheimer's disease
mTOR signaling
PS1
Notch signaling
Hes1
Figures
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