title: Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease.
abstract: 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.
authors.affiliation: KI-Alzheimer Disease Research Center, Karolinska Institutet, Novum, SE 14186 Stockholm, Sweden.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Tang
authors.forename: Erika
authors.initials: E
authors.lastname: Bereczki
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.forename: Chunxia
authors.initials: C
authors.lastname: Li
authors.forename: Xinying
authors.initials: X
authors.lastname: Ji
authors.forename: Rui M
authors.initials: RM
authors.lastname: Branca
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Guan
authors.forename: Peter
authors.initials: P
authors.lastname: Filipcik
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Pei
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; C546842:MTOR protein, human; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C495905:CDK5 protein, human; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2
keywords: Aggregation; Alzheimer Disease; Phosphorylation; Tau; Tau Aggregation; Tau Phosphorylation; Tau Synthesis; Translation; mTOR