mTor mediates tau localization and secretion: Implication for Alzheimer's disease
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 si...
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Published in | Biochimica et biophysica acta Vol. 1853; no. 7; pp. 1646 - 1657 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
01.07.2015
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
•Tau was localized within different organelles in human brains and cellular models.•Up-regulated mTor activity resulted in an increased amount of cytosolic tau.•mTor facilitated tau deposition in different cellular compartments.•mTor mediated tau re-localization to exocytotic vesicles. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0167-4889 0006-3002 1879-2596 1878-2434 |
DOI: | 10.1016/j.bbamcr.2015.03.003 |