Department of Pharmacology and Neuroscience, Institute for Healthy Aging, UNT Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107,
Department of Pharmacology and Neuroscience, UNT Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107.
Front Biosci (Landmark Ed). 2020 Mar 1;25(6):1172-1183. doi: 10.2741/4851.
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.
早老素 1（PS1）蛋白是γ-分泌酶的催化亚基，参与β-淀粉样前体蛋白（APP）的加工，产生 Abeta 肽和 Notch1 受体，在细胞质中释放 Notch 细胞内结构域（NICD）。NICD 迁移到细胞核，通过增加 Hes1 基因的表达引起 Notch 信号。雷帕霉素靶蛋白（mTOR）控制细胞内稳态，其活性被雷帕霉素抑制。Abeta 的积累增加了 mTOR 信号，而降低 mTOR 信号则降低了 Abeta 水平，这表明 mTOR 信号和 Abeta 之间存在相互关系。在阿尔茨海默病（AD）的 3XTg-AD 小鼠模型中给予雷帕霉素可挽救认知缺陷并改善 Abeta 和 Tau 病理学。我们已经剖析了雷帕霉素抑制 PS1 表达和 Notch1 信号的机制。我们的结果表明，雷帕霉素有效地抑制了 mTOR（p-mTOR）的磷酸化，降低了 PS1-mRNA 以及 p-p70S6K1、4EBP1、PS1、NICD 和 Hes1 蛋白水平的表达。因此，雷帕霉素通过抑制 PS1 转录降低了 PS1 蛋白水平和 Notch1 的加工。
