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.

Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain

“…Hyper-activation of mTOR following high energy food intake has been shown to be associated with increased systemic inflammation, and result in insulin resistance through the phosphorylation of p70S6K [20] in animal models. Further, pathological hyper-activation of mTORC1, specifically the levels of p-mTOR and its downstream targets, including p-p70S6K, have been reported to be higher in the brains of Alzheimer’s Disease (AD) clinical samples and mouse models [21-28] of neurodegenerative disease. These studies suggest an association between obesity and activation of mTOR pathway to neuroinflammation.…”

Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy

“…Tau interacts with several proteins in the Akt and mTOR signaling cascades, including Akt [35, 36], ribosomal protein S6 kinase beta-1 (p70S6K) [37, 38], mTOR [39, 40], phosphatase and tensin homolog (PTEN) [41, 42], glycogen synthase kinases 3 alpha and beta (GSK3α, GSK3β) [43-46], and many others, leading to actions such as tau phosphorylation and degradation. For example, GSK3β is known to phosphorylate tau at numerous sites [45].…”

Role of metabolism in neurodegenerative disorders

“…In this context, Tang et al have shown that mTOR overexpression or the lack of its expression is responsible for the altered balance of phosphorylated/non phosphorylated tau, a condition which might facilitate tau deposition [59]. In the brain, the kinase mTOR has been shown to control molecular functions related to cell cycle regulation, A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 9 cell death and several metabolic pathways.…”