The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease

Talboom, Joshua S.; Velázquez, Ramón; Oddo, Salvatore

doi:10.1038/npjamd.2015.8

Cited by 64 publications

(50 citation statements)

References 94 publications

(122 reference statements)

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“…This is considered an acute rapamycin effect rather than a chronic effect. This result agrees with the findings of previous studies showing that acute local administration of rapamycin impairs learning and memory formation [41,43,44,50,54–56]. Although rapamycin was previously reported to be capable of crossing the blood-brain barrier [57], the general whole-body effects of rapamycin and the local effect of rapamycin on the brain should be distinguished because the concentration and localization of rapamycin are considered to differ following peroral versus regional administration.…”

Section: Discussionsupporting

confidence: 93%

The intestinal TORC2 signaling pathway contributes to associative learning in Caenorhabditis elegans

et al. 2017

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Several types of associative learning are dependent upon the presence or absence of food, and are crucial for the survival of most animals. Target of rapamycin (TOR), a kinase which exists as a component of two complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2), is known to act as a nutrient sensor in numerous organisms. However, the in vivo roles of TOR signaling in the nervous system remain largely unclear, partly because its multifunctionality and requirement for survival make it difficult to investigate. Here, using pharmacological inhibitors and genetic analyses, we show that TORC1 and TORC2 contribute to associative learning between salt and food availability in the nematode Caenorhabditis elegans in a process called taste associative learning. Worms migrate to salt concentrations experienced previously during feeding, but they avoid salt concentrations experienced under starvation conditions. Administration of the TOR inhibitor rapamycin causes a behavioral defect after starvation conditioning. Worms lacking either RICT-1 or SINH-1, two TORC2 components, show defects in migration to high salt levels after learning under both fed and starved conditions. We also analyzed the behavioral phenotypes of mutants of the putative TORC1 substrate RSKS-1 (the C. elegans homolog of the mammalian S6 kinase S6K) and the putative TORC2 substrates SGK-1 and PKC-2 (homologs of the serum and glucocorticoid-induced kinase 1, SGK1, and protein kinase C-α, PKC-α, respectively) and found that neuronal RSKS-1 and PKC-2, as well as intestinal SGK-1, are involved in taste associative learning. Our findings shed light on the functions of TOR signaling in behavioral plasticity and provide insight into the mechanisms by which information sensed in the intestine affects the nervous system to modulate food-searching behaviors.

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Section: Discussionsupporting

confidence: 93%

The intestinal TORC2 signaling pathway contributes to associative learning in Caenorhabditis elegans

et al. 2017

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“…First, locomotor deficits in HSP are believed to be associated with degeneration of specific subsets of neurons within the brain and spinal cord. Although the mechanisms underlying the neurodegeneration that is presumed to occur in HSPs are unknown, neurodegeneration in other disorders, such as Alzheimer's, Parkinson's and Huntington's diseases, appear to involve Tor activation (reviewed recently in Talboom et al, 2015) and appear to be sensitive to rapamycin administration. Our results support the notion that the degeneration in atl-mediated HSP might likewise be caused by Tor activation; if so, the development of this HSP would be placed within the same framework as the mechanisms underlying the other neurodegenerative disorders listed above.…”

Section: Cellular Degeneration and Clinical Features In Hspmentioning

confidence: 99%

Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia

Stern

McNew

2017

Journal of Cell Science

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The locomotor deficits in the group of diseases referred to as hereditary spastic paraplegia (HSP) reflect degeneration of upper motor neurons, but the mechanisms underlying this neurodegeneration are unknown. We established a Drosophila model for HSP, atlastin (atl), which encodes an ER fusion protein. Here, we show that neuronal atl loss causes degeneration of specific thoracic muscles that is preceded by other pathologies, including accumulation of aggregates containing polyubiquitin, increased generation of reactive oxygen species and activation of the JNK-Foxo stress response pathway. We show that inhibiting the Tor kinase, either genetically or by administering rapamycin, at least partially reversed many of these pathologies. atl loss from muscle also triggered muscle degeneration and rapamycinsensitive locomotor deficits, as well as polyubiquitin aggregate accumulation. These results indicate that atl loss triggers muscle degeneration both cell autonomously and nonautonomously.

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“…Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that is activated by Akt. It regulates protein synthesis and degradation, cell survival, proliferation and longevity . Thus, dysregulation of mTOR may contribute to disease pathogenesis .…”

Section: Introductionmentioning

confidence: 99%

“…It regulates protein synthesis and degradation, cell survival, proliferation and longevity . Thus, dysregulation of mTOR may contribute to disease pathogenesis . mTOR also plays a role in nutrient sensing and is activated in the liver and other tissues in individuals with obesity and non‐alcoholic fatty liver disease .…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, mTOR activity is important in maintaining normal cognition . Hyperactivation of mTOR leads to cognitive deficits in several clinical cases, such as tuberous sclerosis and Alzheimer's disease (AD) . Interestingly, the administration of rapamycin, an inhibitor of mTOR, offsets cognitive deficits in mouse models of tuberous sclerosis and AD .…”

Section: Introductionmentioning

confidence: 99%

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Chronic administration of theobromine inhibits mTOR signal in rats

Sugimoto

Katakura

Matsuzaki

et al. 2018

Basic Clin Pharma Tox

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Theobromine is a caffeine derivative and the primary methylxanthine in Theobroma cacao. We have shown previously that theobromine inhibits the Akt-mammalian target of rapamycin (mTOR) signal in vitro. In this study, we investigated whether orally administered theobromine could inhibit mTOR activity in rats. mTOR is phosphorylated by Akt. Thus, the level of phosphorylated mTOR was used as an index of mTOR activity. Male Wistar rats were divided into two groups. The control group (CN) was fed a normal diet, while the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 40 days.We measured body-weights and tissue weights, food and water intake, blood count, concentrations of theobromine in the plasma, liver and brain, and the levels of phosphorylated mTOR in the liver and brain. Orally administered theobromine did not affect the body-weights and tissue weights, food and water intake, and blood count as determined by comparison with levels in rats that were fed standard chow. Theobromine was detected in the plasma, liver and brain obtained from TB rats, but was not detected in tissues obtained from CN rats. The phosphorylated mTOR levels in the liver and brain were significantly lower in TB rats than in CN rats. The results suggest that oral theobromine inhibits mTOR signalling in vivo. K E Y W O R D S4E-BP1, Akt, cerebral cortex, liver, mTOR, theobromine

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The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease

Cited by 64 publications

References 94 publications

The intestinal TORC2 signaling pathway contributes to associative learning in Caenorhabditis elegans

The intestinal TORC2 signaling pathway contributes to associative learning in Caenorhabditis elegans

Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia

Chronic administration of theobromine inhibits mTOR signal in rats

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