Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease

• Published in: The Journal of biological chemistry Vol. 288; no. 22; pp. 15556 - 15570
• Main Authors: Tang, Zhi, Bereczki, Erika, Zhang, Haiyan, Wang, Shan, Li, Chunxia, Ji, Xinying, Branca, Rui M, Lehtiö, Janne, Guan, Zhizhong, Filipcik, Peter, Xu, Shaohua, Winblad, Bengt, Pei, Jin-Jing
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 31.05.2013
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Brain - metabolism; Brain - physiology; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Female; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Homeostasis; Humans; Male; Medicin och hälsovetenskap; Middle Aged; Molecular Bases of Disease; Neurons - metabolism; Neurons - pathology; Oncogene Protein v-akt - genetics; Oncogene Protein v-akt - metabolism; Phosphorylation - genetics; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; tau Proteins - genetics; tau Proteins - metabolism; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Aggregation; Phosphorylation; Translation; Tau Synthesis; Tau Phosphorylation; mTOR; Tau; Tau Aggregation; Alzheimer Disease
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M112.435123

Previous evidence from post-mortem Alzheimer disease (AD) brains and drug (especially rapamycin)-oriented in vitro and in vivo models implicated an aberrant accumulation of the mammalian target of rapamycin (mTor) in tangle-bearing neurons in AD brains and its role in the formation of abnormally hyperphosphorylated tau. Compelling evidence indicated that the sequential molecular events such as the synthesis and phosphorylation of tau can be regulated through p70 S6 kinase, the well characterized immediate downstream target of mTor. In the present study, we further identified that the active form of mTor per se accumulates in tangle-bearing neurons, particularly those at early stages in AD brains. By using mass spectrometry and Western blotting, we identified three phosphoepitopes of tau directly phosphorylated by mTor. We have developed a variety of stable cell lines with genetic modification of mTor activity using SH-SY5Y neuroblastoma cells as background. In these cellular systems, we not only confirmed the tau phosphorylation sites found in vitro but also found that mTor mediates the synthesis and aggregation of tau, resulting in compromised microtubule stability. Changes of mTor activity cause fluctuation of the level of a battery of tau kinases such as protein kinase A, v-Akt murine thymoma viral oncogene homolog-1, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and tau protein phosphatase 2A. These results implicate mTor in promoting an imbalance of tau homeostasis, a condition required for neurons to maintain physiological function.