mTor mediates tau localization and secretion: implication for Alzheimer’s disease
Open accessAbstract
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.
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Overactivation of other mTOR pathway proteins is linked to tau pathology.
“Interestingly, an overactivation of other mTOR pathway proteins are also linked to tau pathology.22,23”
From Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia (2020) · cites this paper as [23]
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- Authors
- Tang, Z., Ioja, E., Bereczki, E., Hultenby, K., Li, C., Guan, Z., Winblad, B., & Pei, J.-J.
- Affiliations
- Karolinska Institutet (SE)
- Karolinska University Hospital (SE)
- Capital Medical University (CN)
- Corresponding author
- Pei, Jin-Jing
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 1853
- Issue
- 7
- Pages
- 1646-1657
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2055468625
- Cited by
- 112
- References
- 12
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 7 · 2021: 11 · 2020: 12 · 2019: 12 · 2018: 11 · 2017: 14 · 2016: 9 · 2015: 8
- FWCI
- 10.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gun och Bertil Stohnes Stiftelse
- Karolinska Institutet
- Swedish Brain Power
- Alzheimerfonden
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- mTOR signaling, tau protein, tau hyperphosphorylation, tau secretion, Alzheimer's disease, tauopathy, neurofibrillary tangles, paired helical filaments, subcellular localization, autophagosomes, exocytosis, exosomes, cerebrospinal fluid tau, SH-SY5Y cells
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Autophagy, Cell Membrane, Cytosol, Endoplasmic Reticulum, Female, Golgi Apparatus, Humans, Male, Middle Aged, Mitochondria, Neurons, Subcellular Fractions, Vacuoles, Up-Regulation, Neurofibrillary Tangles, tau Proteins, Protein Transport, Intracellular Space, Cell Line, Tumor, Exosomes, TOR Serine-Threonine Kinases, Protein Aggregation, Pathological
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