Levels of mTOR and its downstream targets 4E‐BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain

  title={Levels of mTOR and its downstream targets 4E‐BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain},
  author={Xu Li and Irina Alafuzoff and Hilkka Soininen and Bengt Winblad and Jin-jing Pei},
  journal={The FEBS Journal},
The pathogenesis of formation of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains is unknown. One of the possibilities might be that translation of tau mRNA is aberrantly regulated in AD brains. In the current study, levels of various translation control elements including total and phosphorylated (p) forms of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E‐BP1), eukaryotic elongation factor 2 (eEF2), and eEF2 kinase were investigated… 

mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons.

It is concluded that striking a new balance by restoring m TORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD.

The role of mTor in the pathogenesis of tau-related pathologies in Alzheimer Disease

It is found that mTor mediates the synthesis and accumulation of tau, resulting in compromised microtubule stability, and the suppression of mTor decreases the rate of cell proliferation assessed by WST.

Mammalian Target of Rapamycin (mTor) Mediates Tau Protein Dyshomeostasis

It is identified that the active form of mTor per se accumulates in tangle-bearing neurons, particularly those at early stages in AD brains, implicate mTor in promoting an imbalance of tau homeostasis, a condition required for neurons to maintain physiological function.

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats

Specific signaling pathways engaged in the development of AD, including a regulatory role by the activation of mTOR in PIC mechanisms are revealed, which is likely to play a beneficial role in modulating neurological deficits in AD.

PPAR Gamma Coactivator 1 Beta (PGC-1β) Reduces Mammalian Target of Rapamycin (mTOR) Expression via a SIRT1-Dependent Mechanism in Neurons

It is demonstrated that Aβ increases the expression of mTOR and p-mTOR at the site of Ser2448, and the stimulation of Aβ is likely to depend on sirtuin 1, PPARγ, and PGC-1β pathway in regulating mTOR expression.

Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice

Deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation.

Molecular interplay between hyperactive mammalian target of rapamycin signaling and Alzheimer’s disease neuropathology in the NS-Pten knockout mouse model

Novel insight is provided into how altered mTOR signaling is linked to AD pathology, without the use of an in-vivo AD model that already displays neuropathological hallmarks of the disease.



Role of protein kinase B in Alzheimer's neurofibrillary pathology

The increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.

Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain

A dramatic increase of phosphorylated eIF4E in Alzheimer's disease is found, especially in those cases with late stages of neurofibrillary changes, and data suggest that the increase of eif4E phosphorylation is involved in formation of Alzheimer neurofibillary changes.

Distribution, Levels, and Activity of Glycogen Synthase Kinase‐3 in the Alzheimer Disease Brain

It is found that GSK-3 is prominently present in neuronal cell bodies and their processes and co-localizes with neurofibrillary changes in AD brain and is significantly increased in the postsynaptosomal supernatant from AD brains as compared to the controls.

Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology

Evidence of increased Akt activation, and hyperphosphorylation of critical Akt substrates in AD brain, which link to AD pathogenesis is provided, suggesting that treatments aiming to activate the pathway in AD need to be considered carefully.

Distribution of Active Glycogen Synthase Kinase 3β (GSK-3β) in Brains Staged for Alzheimer Disease Neurofibrillary Changes

Direct in situ evidence is found that neurons with tangle-like inclusions positive for active, but not inactive, GSK-3β appear initially in the Pre-α layer of the entorhinal cortex and extend to other brain regions, coincident with the sequence of the development of neurofibrillary changes.

Mechanism of zinc‐induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3β in SH‐SY5Y neuroblastoma cells

Investigation in serum‐deprived SH‐SY5Y neuroblastoma cells found that zinc could induce an increase of phosphorylated p70S6K, p‐PKB, p-GSK‐3β, ERK1/2, JNK, p38 and p70’S6 kinase, that are consequently involved in tau changes in SH‐ SY5Y cells.

Brain Levels of Microtubule‐Associated Protein τ Are Elevated in Alzheimer's Disease: A Radioimmuno‐Slot‐Blot Assay for Nanograms of the Protein

The studies indicate that the abnormal phosphorylation—not a decrease in the level of τ—is a likely cause of neurofibrillary degeneration in AD.

Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration.

Data indicate that increased activation of the stress related kinases JNK and p38 occurs very early in the disease and might be involved in the intraneuronal protein phosphorylation/dephosphorylation imbalance that leads to neurofibrillary degeneration in Alzheimer disease.