Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1853, Issue 7, Pages 1646-1657Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2015.03.003
Keywords
mTor; Tau secretion; Autophagy; Tau phosphorylation; Alzheimer's disease
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Funding
- Karolinska Institutet Research funds
- Dementia Foundation
- Alzheimerfonden
- Wallenberg foundation
- Gun and Bertil Stohnes Foundation
- Gamla Tjanarinnor Foundation
- Karolinska Institutet Strategic Neuroscience Program
- Swedish Brain Power Programme
- Sheikha Salama Bint Hamdan Al Nahyan Foundation
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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 rnTor, 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. (C) 2015 Elsevier B.V. All rights reserved.
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