title: mTor mediates tau localization and secretion: Implication for Alzheimer's disease.
abstract: Abnormally hyperphosphorylated tau aggregates form paired helical filaments (PHFs) in neurofibrillary tangles, a key hallmark of Alzheimer's disease (AD) and other tauopathies. The cerebrospinal fluid (CSF) levels of soluble total tau and phospho-tau from clinically diagnosed AD patients are significantly higher compared with controls. Data from both in vitro and in vivo AD models have implied that an aberrant increase of mammalian target of rapamycin (mTor) signaling may be a causative factor for the formation of abnormally hyperphosphorylated tau. In the present study, we showed that in post-mortem human AD brain, tau was localized within different organelles (autophagic vacuoles, endoplasmic reticulum, Golgi complexes, and mitochondria). In human SH-SY5Y neuroblastoma cells stably carrying different genetic variants of mTor, we found a common link between the synthesis and distribution of intracellular tau. mTor overexpression or the lack of its expression was responsible for the altered balance of phosphorylated (p-)/-non phosphorylated (Np-) tau in the cytoplasm and different cellular compartments, which might facilitate tau deposition. Up-regulated mTor activity resulted in a significant increase in the amount of cytosolic tau as well as its re-localization to exocytotic vesicles that were not associated with exosomes. These results have implicated that mTor is involved in regulating tau distribution in subcellular organelles and in the initiation of tau secretion from cells to extracellular space.
authors: Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden; Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
authors: Zhi
authors: Z
authors: Tang
authors: Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden.
authors: Eniko
authors: E
authors: Ioja
authors: Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden.
authors: Erika
authors: E
authors: Bereczki
authors: Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE 141 86 Stockholm, Sweden.
authors: Kjell
authors: K
authors: Hultenby
authors: Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden.
authors: Chunxia
authors: C
authors: Li
authors: Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden; Department of Pathology, Guiyang Medical College, Guiyang 550004, Guizhou, China; Molecular Biology, Guiyang Medical College, Guiyang 550004, Guizhou, China.
authors: Zhizhong
authors: Z
authors: Guan
authors: Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden.
authors: Bengt
authors: B
authors: Winblad
authors: Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden; Department of Neurology, Xuan Wu Hospital, Capital Medical University, China; Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100053, China. Electronic address: Jin-Jing.Pei@ki.se.
authors: Jin-Jing
authors: JJ
authors: Pei
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D055354:Exosomes / Q000378:metabolism; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Alzheimer's disease; Autophagy; Tau phosphorylation; Tau secretion; mTor